Systems and methods for selective auto-retroperfusion along with regional mild hypothermia

ABSTRACT

Systems and methods for selective auto-retroperfusion along with regional mild hypothermia. In at least one embodiment of a system for providing a retroperfusion therapy to a venous vessel of the present disclosure, the system comprises a catheter for controlling blood perfusion pressure, the catheter comprising a body having a proximal open end, a distal end, a lumen extending between the proximal open end and the distal end, and a plurality of orifices disposed thereon, each of the orifices in fluid communication with the lumen, and at least one expandable balloon, each of the at least one expandable balloons coupled with the body, having an interior that is in fluid communication with the lumen, and adapted to move between an expanded configuration and a deflated configuration, and a flow unit for regulating the flow and pressure of a bodily fluid, and a regional hypothermia system operably coupled to the catheter, the regional hypothermia system operable to reduce and/or regulate a temperature of the bodily fluid flowing therethrough.

PRIORITY

The present application is related to, claims the priority benefit of,and is a U.S. continuation-in-part patent application of, U.S. patentapplication Ser. No. 13/965,565, filed Aug. 13, 2013 and issued as U.S.Pat. No. 9,724,232 on Aug. 8, 2017, which (a) is related to, and claimsthe priority benefit of, U.S. Provisional Patent Application Ser. No.61/682,351, filed Aug. 13, 2012, and (b) is related to, claims thepriority benefit of, and is a continuation-in-part application of, U.S.patent application Ser. No. 13/705,101, filed Dec. 4, 2012 and issued asU.S. Pat. No. 9,108,000 on Aug. 18, 2015, which is related to, claimsthe priority benefit of, and is a continuation application of, U.S.application Ser. No. 12/715,100, filed Mar. 1, 2010 and issued as U.S.Pat. No. 8,322,347 on Dec. 4, 2012, which is related to, claims thepriority benefit of, and is a continuation application of, U.S. patentapplication Ser. No. 12/715,046, filed Mar. 1, 2010 and issued as U.S.Pat. No. 8,241,248 on Aug. 14, 2012, which is related to, and claims thepriority benefit of, U.S. Provisional Patent Application Ser. No.61/156,458, filed on Feb. 27, 2009. The contents of each of theseapplications are hereby incorporated by reference in their entirety intothis disclosure.

BACKGROUND

Globally, stroke has a major impact on public health as it is the secondmost common cause of death and a major cause of disability. It isestimated that around 700,000 people experience a transient ischemicattack or stroke annually in the United States alone. Of those 700,000people, it is estimated about 200,000 experience a recurrent stroke at alater date. As such, stroke survivors as a group have an increased riskof experiencing an additional stroke(s) and, unsurprisingly, haveincreased mortality and morbidity rates.

National projections for the period between 2006 and 2025 predict around1.5 million new cases of ischemic stroke in men and 1.9 million newcases in women. The total projected cost of stroke and the resultantdisability associated therewith is estimated to be around $2.2 trillionin the United States alone, including direct and indirect costs such asambulance services, initial hospitalization, rehabilitation, nursinghome costs, outpatient visits, drugs, informal care-giving, and lostpotential earnings. Accordingly, the cost of this illness to society inboth health care and lost productivity is enormous, and the extendedcomplications associated with surviving even one stroke event adverselyinfluences both quality of life, and the morbidity and mortality of theindividual stroke survivor.

Viability of the cerebral tissue depends on cerebral blood flow. Duringa stroke, a portion of brain tissue known as the ischemic lesion isdeprived of sufficient blood flow due to an arterial occlusion (i.e. ablood clot). Within the ischemic cerebrovascular bed caused by an acuteischemic stroke, there are two major zones of injury: the core ischemiczone and the ischemic penumbra. In the core zone, which is an area ofsevere ischemia (blood flow reduced to below 15-20 ml/100 g/minute), theloss of an adequate supply of oxygen and glucose results in the rapiddepletion of energy stores resulting in death of the brain tissue. Asneurons die within a few minutes of oxygen deprivation, neuronal deathbegins to occur in areas of no blood flow within minutes of strokeonset, thus leaving the tissue of the core ischemic zone unable tofunction.

Surrounding such areas of necrosis is a transitional region ofhypoperfused, electronically silent tissue that barely receives enoughblood flow to keep the neurons alive. Brain cells within thistransitional region, the penumbra, are functionally compromised, but notyet irreversibly damaged. Accordingly, the ischemic penumbra may remainviable for several hours after ischemic onset and therefore is the majorfocus of most therapeutic procedures for resuscitation of acute strokepatients.

When the systemic pressure of the brain lowers, cerebral perfusionautoregulation reflexes allow for vasodilation in order to keep aconstant cerebral blood flow. This vascular dilation leads in turn to anincreased cerebral blood volume, at least within the salvageablepenumbra. (Contrary to the penumbral regions, the autoregulationprocesses are compromised in the area of the core ischemic infarctitself and therefore both CBV and cerebral blood flow are diminishedthereto.) In the penumbra, cerebral perfusion autoregulation reflexesautomatically adjust the regional cerebral blood volume and ensurecerebral blood flow stability despite changes in systemic arterialpressure caused by the underlying arterial occlusion. In this manner,the regional cerebral blood volume may be greater than 2.5 millilitersper 100 g in the penumbral area.

Through mapping the cerebral blood volume and the cerebral blood flow,it is possible to locate the penumbra-infarct area regions of the brain,with diminution in both cerebral blood flow and cerebral blood volumecorresponding to the core ischemic zone and regions with a decreasedcerebral blood flow, yet increased of cerebral blood volumecorresponding to the penumbra. Recognition of the penumbra throughmodern neuroimaging techniques (e.g., computed tomography and magneticresonance imaging) may be used to identify patients who are more likelyto benefit from therapeutic intervention.

Typically, a window of viability exists during which the neurons withinthe ischemic penumbra may recover if the area is reperfused. This windowof viability exists because the penumbral region is supplied with bloodthrough collateral arteries anastomosing with branches of the occludedvascular tree and is subjected to increased cerebral blood volume aspreviously discussed. However, if reperfusion is not establishedrelatively quickly following the acute attack, over time irretrievableinfarction will progressively replace the cells in the penumbral region.This replacement rate varies according to the collateral circulationlevels and is often patient and event specific. On average, a cliniciantypically has between about two (2) to three (3) hours following theonset of an acute ischemic stroke event during which to reperfuse theischemic penumbral region; however, this timeframe may be shorter orextend as long as twenty-two (22) hours from acute onset, depending onthe particular patient and other factors. Because the penumbra has thepotential for recovery and survival of the neurons in the penumbralregion is associated with better prognostics, the penumbra is animportant therapeutic target to be considered for interventional therapyin acute ischemic stroke patients.

Despite advances in the understanding of stroke pathogenesis, untilrecently, no specific therapeutic procedures have been available forimproving outcomes in acute stroke patients. However, due to recenttherapeutic developments, the morbidity and mortality of acute strokepatients has seen an overall decline. For example, the availability ofgeneral acute management in a stroke unit, medication through aspirinwithin forty-eight (48) hours of acute onset, and the intravenous use ofthrombolytic therapies within three (3) hours of acute onset havecontributed to the reduction seen in the morbidity and mortality ofacute stoke patients. While these therapies have shown favorableresults, all of these therapeutic procedures require that the patient istreated immediately after or within a short time of stroke onset inorder to prevent or minimize neuron death. Accordingly, a need exists toextend the window of time during which the penumbra is viable, and thusthe time during which the thrombolytic therapy may be effective, inorder to further improve efficacy of the procedures and reduceassociated complication rates.

There is currently little understanding of how to use prophylactictherapies in patients suffering from an acute ischemic stroke. Forexample, the rigid time window where the penumbral region remains viablegreatly limits the availability of thrombolytic treatment in themajority of cases. Further, for more than two (2) decades, neurologistshave sought a drug that protects ischemic brain tissue from cell deathwith little success; the list of pharmaceuticals tested in Phase II andPhase III trials is extensive, yet none have proved effective in humans.Other neuroprotective agents such as radical scavengers, calciumantagonists, sodium or potassium channel blockers, cell membranestabilizers, anti-inflammatory agents, anti-adhesion molecules, andglycine-, AMPA- and serotonin-receptor antagonists have proven tosignificantly reduce the infarct volume in animal models, yet also werefound ineffective in clinical trials. One reason such pharmaceuticaland/or thrombolytic therapies have been found ineffective in humans isthat it is unlikely that the drugs, especially neuroprotective agents,can reach high enough pharmacological levels in the penumbral region toprevent the progression of tissue damage therein prior to the onset ofcellular death. Accordingly, the combination of neuroprotective drugtherapies and thrombolytic treatments in particular may be mandatory toovercome these hurdles within the short three (3) hour window where thecells remain viable.

One technique that has not conventionally been applied in the treatmentof stroke victims is retrograde cerebral perfusion (“RCP”) therapies.RCP has been applied for more than a decade in connection with aorticarch surgeries requiring hypothermic circulatory arrest. One of thefirst uses of RCP was reported in 1994, for periods lasting betweentwenty-seven (27) and eighty-one (81) minutes. All of the patients whowere the subjects of that study returned to consciousness within four(4) hours of the procedure and there was no record of detectableneurologic defects that arose postoperatively. As previously noted,since these initial trials, RCP has been used extensively in connectionwith similar procedures. Recent clinical reports suggest thatcirculation management using RCP in combination with hypothermiccirculatory arrest has even decreased the overall rate of stroke andoperative mortality associated with aortic arch operations.

The advantages of RCP for use in connection with aortic arch surgerieshave been well delineated, such as continuous delivery of metabolicsubstrates to the brain (e.g., oxygen and other cellular nutrients),removal of toxic metabolites and possible embolism (i.e. air orparticulates), and better preservation of uniform hypothermia. Further,other theoretical advantages of RCP have been suggested, such asflushing of gaseous or atheromatous debris and the ease of establishmentwithout the need for any additional cannulas.

Although RCP has been very successful for patients undergoingcirculatory arrest in surgery, a bridge reperfusion therapy used inconjunction with thrombolytics and/or other pharmaceuticals for strokepatients does not currently exist. Accordingly, a need exists for adevice, system and method for providing stroke patients with sufficientblood flow to the penumbra in order to nourish the brain tissue suchthat thrombolytic or other pharmaceutical agents are provided with asufficient amount of time in which they can establish the necessarypharmacological concentrations in the area of interest and effectivelyperform the intended pharmacological function.

BRIEF SUMMARY

Devices and systems are described for providing retroperfusion andautoretroperfusion therapies to a brain. In certain embodiments, acatheter for controlling blood perfusion pressure is provided. Thecatheter comprises a body, at least one expandable balloon and at leastone sensor coupled with the body. The body of the catheter comprises aproximal open end, a distal end, a lumen extending between the proximalopen end and the distal end, and a plurality of orifices disposedthereon. Each of the orifices is in fluid communication with the lumenof the catheter body. In at least one embodiment, the body of thecatheter is configured for placement within a venous vessel. Further,the lumen of the body may optionally be configured to slidably receiveat least one guidewire therethrough, and the distal end of the body maybe configured to allow the at least one guidewire to extendtherethrough.

Each of the at least one expandable balloons of the catheter is coupledwith the body and comprises an interior that is in fluid communicationwith the lumen. Further, each expandable balloon is adapted to movebetween an expanded configuration and a deflated configuration. The bodyof the catheter may further comprise one or more pores disposed thereonto facilitate fluid communication between the lumen and the interior ofteach of the at least one expandable balloons. In this embodiment, eachof the at least one expandable balloons may be adapted to move from thedeflated configuration to the expanded configuration when a fluid flowsthrough the lumen of the body, through the one or more pores, and intothe interior of the expandable balloon.

Each of the at least one sensors of the catheter is coupled with thedistal end of the body and adapted to gather data relating to a fluidflowing through the lumen. Further, in at least one embodiment, the atleast one sensor is adapted to transmit the gathered data to a remotedevice. The transmission of gathered data to the remote device may beachieved in various different manners. In at least one embodiment, atleast one of the at least one sensors is coupled with a sensor capable.The sensor capable may be disposed within the interior of the lumen ofthe catheter such that the sensor cable extends through the proximal endof the body and is adapted to transmit the gathered data to the remotedevice.

The catheter described herein may further comprise a sheath. The sheathcomprises a proximal end, a distal end, and an interior. In at least oneembodiment, the interior of the sheath is configured to slidably receivethe body of the catheter therein.

A flow unit for regulating the flow and pressure of a fluid is alsodescribed herein. The flow unit comprises an elongated body having anopen proximal end, an open distal end, an interior extending between theopen proximal end and the open distal end. The flow unit furthercomprises a chamber surrounding at least a portion of the elongatedbody. The chamber comprises an interior and at least one port in fluidcommunication with the interior of the chamber which is adapted tocouple with a fluid source. The chamber of the flow unit is adapted toexpand and deflate. In at least one embodiment, the section of theinterior of the elongated body associated with the portion surrounded bythe chamber comprises a first diameter when the chamber is deflated anda second diameter when the chamber is expanded. Here, the seconddiameter is less than the first diameter, such that the chamber reducesthe size of the interior of the elongated body when the chamber isexpanded. Further, the interior of the chamber may be adapted to exert acompressive force on the portion of the elongated body surroundedthereby.

The flow unit further comprises at least one sensor disposed at or nearthe distal end of the elongated body of the flow unit. Each of the atleast one sensors is adapted to gather data relating to the fluidflowing through the interior of the elongated body. In at least oneembodiment of the flow unit, one or more of the at least one sensors isadapted to transmit the gathered data to a remote device. For example,and without limitation, the at least one sensor may be electronicallycoupled via a wire with the remote device.

In certain embodiments, the remote device may comprise a computer or anyother processor known in the art. The remote device may be incommunication with the fluid source coupled with the interior of thechamber via the at least one port. In at least one embodiment, the fluidsource is adapted to inject or withdraw fluid—which may be a liquid or agas—from the interior of the chamber in response to the gathered datareceived from the at least one sensor of the flow unit.

Systems for providing a retroperfusion therapy to a venous vesselcomprising the above-described components are also provided herein.Specifically, a system for providing a retroperfusion therapy to avenous vessel comprises the catheter for controlling blood perfusionpressure and the flow unit for regulating the flow and pressure of afluid, both of which are described above. In operation, the open distalend of the flow unit is coupled with the open proximal end of the bodyof the catheter such that fluid communication is established between thelumen of the catheter and the interior of the elongated body of the flowunit.

The system may further comprise a source of arterial blood flowcomprising a proximal end, a distal end and an interior extendingbetween the proximal end and the distal end. The distal end of thesource of arterial blood flow is configured to couple with the proximalend of the elongated body of the flow unit. Each of the proximal end,the distal end and the interior of the source of arterial blood flow isconfigured to allow arterial blood to flow therethrough.

The remote device of the system may be in communication with the fluidsource coupled with the flow unit. Further, the remote device may beadapted to receive the gathered data from the at least one sensor of theflow unit and process the gathered data to ascertain if the gathereddata falls within one or more parameters. For example, in at least oneembodiment, the one or more parameters may comprise flow rate of a fluidflowing through the interior of the elongated body of the flow unit,pressure of the fluid flowing through the interior of the elongated bodyof the flow unit, and/or perfusion rate of the fluid into the venousvessel. In at least one embodiment, the remote device is also adapted toautomatically affect the flow of fluid to or from the fluid source whenthe gathered data falls outside of the one or more parameters.

The system may further comprise a connection assembly for providing asterile environment. In at least one embodiment, the connection assemblycomprises a cover, at least one valve in fluid communication with thecover, and at least one flushing port in fluid communication with thegas supply and the cover. The cover of the connection assembly comprisesa body portion, a limb component extending from the body portion, and aninterior extending between the body portion and the limb component. Inat least one embodiment, the cover is corrugated. The interior of thecover configured to encase the distal end of the elongated body of theflow unit and the proximal end of the body of the catheter therein andfurther is in fluid communication with the at least one flushing portand the at least one valve of the connection assembly. Furthermore, theinterior of the cover may be adapted to slidably receive at least oneguidewire therethrough.

The at least one valve of the connection assembly is adapted to draingas from within the interior of the cover. The at least one valve mayoptionally be adapted to automatically drain gas from within theinterior of the cover when the pressure within the interior of the coveris greater than a set value. Furthermore, in at least one embodiment,the at least one valve comprises a one-way valve.

Kits comprising the above-described system are also disclosed herein.For example, in at least one embodiment, a kit comprising the followingis described: a catheter for controlling blood perfusion pressure, thecatheter comprising a body having a proximal open end, a distal end, alumen extending between the proximal open end and the distal end, and aplurality of orifices disposed thereon, each of the orifices in fluidcommunication with the lumen, and at least one expandable balloon, eachof the at least one expandable balloons coupled with the body, having aninterior that is in fluid communication with the lumen and adapted tomove between an expanded configuration and a deflated configuration; anda flow unit for regulating the flow and pressure of a fluid, the flowunit comprising an elongated body having an open proximal end, an opendistal end, an interior extending between the open proximal end and theopen distal end, and a chamber surrounding at least a portion of theelongated body, the chamber adapted to expand and deflate and comprisingan interior and at least one port, the at least one port in fluidcommunication with the interior of the chamber and adapted to couplewith a fluid source, and at least one sensor coupled with the distal endof the elongated body, each of the at least one sensors adapted togather data and transmit the gathered data to a remote device. The kitmay additionally comprise at least one guidewire and/or the connectionassembly described herein for providing a sterile environment.

Methods for delivering a retroperfusion therapy to an ischemic area of abrain are also provided herein. In at least one embodiment, such amethod comprises the steps of: identifying the location of a penumbralregion within a brain; re-routing arterial blood flow from an arteryinto the proximal end of a first catheter for receiving arterial bloodflow, the first catheter comprising a proximal end for receiving thearterial blood flow, a distal end for allowing the arterial blood flowto flow therethrough and an interior extending between the proximal endand the distal end; inserting a first guidewire into a vein andadvancing the guidewire through the vein into the penumbral region ofthe brain; advancing a second catheter over the first guidewire, throughthe vein and into the penumbral region of the brain, the second cathetercomprising an open proximal end, a distal end, an interior extendingbetween the open proximal end and the distal end, and a plurality oforifices disposed thereon, each of the orifices in fluid communicationwith the interior of the second catheter; coupling the proximal end ofthe second catheter with a flow unit, the flow unit comprising anelongated body having an open proximal end configured to couple with thedistal end of the first catheter, an open distal end configured tocouple with the open proximal end of the second catheter, an interiorextending between the open proximal end and the open distal end andconfigured to allow arterial blood to flow therethrough, and a chambercoupled with the elongated body and configured to regulate the flow rateand pressure of the arterial blood flow flowing through the interior ofthe flow unit; coupling the distal end of the first catheter with theproximal end of the flow unit such that the interior of the firstcatheter and the interior of the flow unit are in fluid communication;supplying the penumbral region of the brain with arterial blood flow byallowing the arterial blood to flow in a pulsatile fashion through thefirst catheter, into and through the interior of the flow unit, into andthrough the second catheter, and into the vein at the location withinthe penumbral region; and regulating the pressure and flow rate of thearterial blood flowing through the interior of the elongated body of theflow unit through operation of the chamber.

In certain embodiments of the method, the interior of the flow unit maycomprise a diameter. In this embodiment, the step of regulating thepressure and flow rate of the arterial blood flowing through theinterior of the elongated body of the flow unit through operation of thechamber may additionally comprise adjusting the diameter of the interiorof the elongated body of the flow unit to affect the pressure and/orflow rate of the arterial blood flowing therethrough.

Further, in at least one embodiment of the method, the flow unit furthercomprises at least one sensor disposed at or near the open distal end ofthe elongated body and the first catheter further comprises at least onesensor disposed at or near the distal end thereof. Here, each of the atleast one sensors is adapted to gather data and transmit the gathereddata to a remote device. In this at least one embodiment, the method mayfurther comprise the step of using the remote device to monitor the datagathered by the at least one sensor of the flow unit and the at leastone sensor of the first catheter. Additionally, at least one embodimentof the method further comprises the step of processing the gathered datafrom the flow unit and the second catheter to ascertain if the gathereddata falls within one or more programmed parameters.

The second catheter of the method may further comprise at least oneexpandable balloon, each of the at least one expandable balloons coupledwith the first catheter, having an interior in fluid communication withthe interior of the second catheter through one or more pores andadapted to move between an expanded configuration and a deflatedconfiguration. In this at least one embodiment, wherein when the atleast one balloon of the second catheter is in the expandedconfiguration, the at least one balloon of the second catheter occludesthe vein and prevents antegrade flow of the arterial blood therethrough.Additionally, at least one embodiment of the method described hereinfurther comprises the step of moving the at least one balloon of thesecond catheter from the deflated configuration to the expandedconfiguration in accordance with the pulsatile flow of the arterialblood through the interior of the second catheter.

In certain embodiments, the step of regulating the pressure and flowrate of the arterial blood flowing through the interior of the elongatedbody of the flow unit through operation of the chamber is automaticallyinitiated by the remote device when the gathered data falls outside ofthe one or more programmed parameters. Further, the interior of theelongated body of the flow unit may comprise a diameter and the chamberof the flow unit surrounding at least a portion of the elongated body ofthe flow unit may comprises an interior defining a volume, and may beadapted to expand when the volume is increased and deflate when thevolume is decreased; and the step of regulating the pressure and flowrate of the arterial blood flowing through the interior of the elongatedbody of the flow unit through operation of the chamber further maycomprise adjusting the volume of the interior of the chamber such thatthe chamber compresses a section of the interior of the elongated bodyassociated with the portion surrounded by the chamber thereby reducingthe diameter of the interior of the elongated body.

The methods described herein may further comprise the step of definingan inherent pressure and flow cycle of the arterial blood flowingthrough the flow unit and establishing a sequence of injecting andwithdrawing fluid from the interior of the chamber of the flow unit.Alternatively or additionally, the methods may further comprise the stepof delivering a pharmaceutical agent to the brain.

In at least one embodiment of the method, the step of coupling theproximal end of the second catheter with a flow unit may be performed ina sterile environment provided by the connection assembly previouslydescribed herein. Here, the step of the method comprising coupling theproximal end of the second catheter with a flow unit may be performed ina sterile environment provided by a connection assembly comprisesflushing the interior of the cover with a sterile gas. Furthermore, inat least one embodiment, the at least one valve of the connectionassembly is adapted to automatically drain gas from within the interiorof the cover when pressure within the interior of the cover is greaterthan a set value and the method further comprises the step ofmaintaining the pressure within the interior of the cover throughoperation of at least one of the at least one valves. Further, in the atleast one embodiment of the connection assembly where the interior ofthe cover is configured to receive one or more guidewires therethrough,the method may further comprise the steps of inserting a secondguidewire into a vein; advancing the second guidewire through the veininto a location proximate to the flow unit and the open proximal end ofthe second catheter; and advancing the connection assembly over thesecond guidewire, through the vein and to the location.

In those embodiments of the system further comprising the sheath, themethod may further comprise the step of sliding the sheath over thesecond catheter such that one or more of the plurality of orifices areblocked and arterial blood flow is prevented from flowing through theblocked orifice(s).

In various catheters, flow units, systems, kits and/or methods of thepresent disclosure, the catheters, flow units, systems, and/or kitscomprising the same and/or components of the same, further comprise aregional hypothermia system of the present disclosure operably coupledthereto, the regional hypothermia system operable to reduce and/orregulate the temperature of a fluid flowing therethrough, such as blood,and/or operable to reduce and/or regulate the temperature of a vessel, atissue, and/or an organ at or near the blood. In other embodiments, theregional hypothermia system comprises a heat exchanger configured toreduce and/or regulate the temperature of the fluid. In variousembodiments, one or more components of the regional hypothermia systemuses a cooling product to reduce and/or regulate the temperature of thefluid. In any number of embodiments, the devices further comprise one ormore temperature sensors coupled thereto, the one or more temperaturesensors operable to detect a temperature of the blood, the vessel, thetissue, and/or the organ. In various embodiments, the devices furthercomprise a remote module in wired or wireless communication with the oneor more temperature sensors, the remote module operable to andconfigured to receive the detected temperature(s) and process the sameto regulate, reduce, and/or increase the temperature of the blood, thevessel, the tissue, and/or the organ by way of altering the operation ofthe regional hypothermia system.

In at least one embodiment of a hypothermia kit of the presentdisclosure, the hypothermia kit comprises a regional hypothermia systemof the present disclosure, and a catheter, flow unit, system, and/or kitcomprising the same and/or components of the same. In variousembodiments, the hypothermia kit is useful to treat a condition of amammalian tissue and/or organ by way of reducing blood, other fluid,tissue, and/or organ temperature and/or regulating the temperature ofthe same.

In at least one embodiment of a system for providing a retroperfusiontherapy to a venous vessel (a system) of the present disclosure, thesystem comprises a catheter for controlling blood perfusion pressure,the catheter comprising a body having a proximal open end, a distal end,a lumen extending between the proximal open end and the distal end, anda plurality of orifices disposed thereon, each of the orifices in fluidcommunication with the lumen, and at least one expandable balloon, eachof the at least one expandable balloons coupled with the body, having aninterior that is in fluid communication with the lumen, and adapted tomove between an expanded configuration and a deflated configuration, anda flow unit for regulating the flow and pressure of a bodily fluid, anda regional hypothermia system operably coupled to the catheter, theregional hypothermia system operable to reduce and/or regulate atemperature of the bodily fluid flowing therethrough. In anotherembodiment, the regional hypothermia system is further operable toreduce and/or regulate a temperature of a portion of a mammalian body,the portion selected from the group consisting of a vessel, a tissue,and an organ. In yet another embodiment, the regional hypothermia systemcomprises a heat exchanger configured to reduce and/or regulate thetemperature of the bodily fluid. In an additional embodiment, one ormore components of the regional hypothermia system uses a coolingproduct to reduce and/or regulate the temperature of the bodily fluid.In yet an additional embodiment, the system further comprises one ormore temperature sensors coupled to the device, the one or moretemperature sensors operable to detect the temperature of the bodilyfluid.

In at least one embodiment of a system for providing a retroperfusiontherapy to a venous vessel (a system) of the present disclosure, theregional hypothermia system further comprises a remote module in wiredor wireless communication with the one or more temperature sensors, theremote module operable to and configured to receive the detectedtemperature(s) and process the same to regulate, reduce, and/or increasethe temperature of the bodily fluid by way of altering an operation ofthe regional hypothermia system. In an additional embodiment, the systemfurther comprises an arterial blood flow device comprising a proximalend, a distal end configured to couple with the proximal end of theelongated body of the flow unit, and an interior extending between theproximal end and the distal end, the proximal end, the distal end andthe interior each configured to allow arterial blood to flowtherethrough. In yet an additional embodiment, the flow unit comprisesan elongated body having an open proximal end, an open distal endcoupled with the open proximal end of the body of the catheter, aninterior extending between the open proximal end and the open distal endof the elongated body, and a chamber surrounding at least a portion ofthe elongated body, the chamber adapted to expand and deflate andcomprising an interior and at least one port in fluid communication withthe interior of the chamber and adapted to couple with a fluid source,and at least one sensor disposed at or near the distal end of theelongated body, each of the at least one sensors adapted to gather datafrom the fluid flowing through the interior of the elongated body; andIn another embodiment, at least one of the at least one sensors of theflow unit is adapted to transmit the gathered data to a remote device.In yet another embodiment, the system further comprises a connectionassembly for providing a sterile environment, the connection assemblycomprising a cover comprising a body portion, a limb component extendingfrom the body portion, and an interior extending between the bodyportion and the limb component, the interior configured to encase thedistal end of the elongated body of the flow unit and the proximal endof the body of the catheter therein, at least one flushing port in fluidcommunication with a gas supply and the interior of the cover, and atleast one valve in fluid communication with the interior of the cover,the at least one valve adapted to drain gas from within the interior ofthe cover.

In at least one embodiment of a system for providing a retroperfusiontherapy to a venous vessel (a system) of the present disclosure, thesystem comprises a catheter for controlling blood perfusion pressure,the catheter comprising a body having a proximal open end, a distal end,a lumen extending between the proximal open end and the distal end, anda plurality of orifices disposed thereon, each of the orifices in fluidcommunication with the lumen, and at least one expandable balloon, eachof the at least one expandable balloons coupled with the body, having aninterior that is in fluid communication with the lumen, and adapted tomove between an expanded configuration and a deflated configuration, aflow unit for regulating the flow and pressure of a bodily fluid, theflow unit comprising an elongated body having an open proximal end, anopen distal end coupled with the open proximal end of the body of thecatheter, an interior extending between the open proximal end and theopen distal end of the elongated body, and a chamber surrounding atleast a portion of the elongated body, the chamber adapted to expand anddeflate and comprising an interior and at least one port in fluidcommunication with the interior of the chamber and adapted to couplewith a fluid source, and at least one sensor disposed at or near thedistal end of the elongated body, each of the at least one sensorsadapted to gather data from the bodily fluid flowing through theinterior of the elongated body, and a regional hypothermia systemoperably coupled to the catheter and/or the flow unit, the regionalhypothermia system operable to reduce and/or regulate a temperature ofthe bodily fluid flowing through the system. In another embodiment, thesystem further comprises a source of arterial blood flow comprising aproximal end, a distal end configured to couple with the proximal end ofthe elongated body of the flow unit, and an interior extending betweenthe proximal end and the distal end, the proximal end, the distal endand the interior each configured to allow arterial blood to flowtherethrough. In yet another embodiment, at least one of the at leastone sensors of the flow unit is adapted to transmit the gathered data toa remote device. In an additional embodiment, the catheter furthercomprises at least one sensor coupled with the distal end of the body,each of the at least one sensors adapted to gather data on the bodilyfluid flowing through the lumen of the catheter and transmit thegathered data to a remote device.

In at least one embodiment of a system for providing a retroperfusiontherapy to a venous vessel (a system) of the present disclosure, theregional hypothermia system comprises a heat exchanger configured toreduce and/or regulate the temperature of the bodily fluid. In anotherembodiment, the system further comprises one or more temperature sensorscoupled to the catheter and/or the flow unit, the one or moretemperature sensors operable to detect the temperature of the bodilyfluid.

In at least one embodiment of a flow unit for regulating the flow andpressure of a fluid (a flow unit) of the present disclosure, the flowunit comprises an elongated body having an open proximal end, an opendistal end, an interior extending between the open proximal end and theopen distal end, and a chamber surrounding at least a portion of theelongated body, the chamber adapted to expand and deflate and comprisingan interior and at least one port in fluid communication with theinterior of the chamber and adapted to couple with a fluid source, andat least one sensor disposed at or near the distal end of the elongatedbody, each of the at least one sensors adapted to gather data relatingto a bodily fluid flowing through the interior of the elongated body,wherein the flow unit is configured to be coupled to a catheter forcontrolling blood perfusion pressure, and wherein the flow unit isfurther configured for operation in connection with a regionalhypothermia system operably coupled to the catheter and/or the flowunit, the regional hypothermia system operable to reduce and/or regulatea temperature of the bodily fluid flowing therethrough. In an additionalembodiment, one or more of the at least one sensors is adapted totransmit the gathered data to a remote device. In yet an additionalembodiment, a section of the interior of the elongated body associatedwith the portion surrounded by the chamber comprises a first diameterwhen the chamber is deflated and a second diameter when the chamber inexpanded, the second diameter being less than the first diameter. Inanother embodiment, when the chamber is expanded, the interior of thechamber is adapted to exert a compressive force on the portion ofelongated body surrounded thereby.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a side view of one embodiment of a catheter for deliveringarterial blood within a venous vessel.

FIG. 2 shows a side view of the distal end of the catheter of FIG. 1.

FIG. 3 shows the catheter of FIG. 1 coupled with a sheath.

FIG. 4 shows a schematic view of a flow unit for use in connection withthe catheter of FIG. 1 to achieve regulation of arterial blood flow andpressure.

FIG. 5 shows a retroperfusion system for providing a retroperfusiontherapy to an ischemic area of a brain.

FIGS. 6A and 6B show cross-sectional views of the flow unit of FIG. 4wherein the chamber thereof is in an inflated configuration (FIG. 6A)and in a deflated configuration (FIG. 6B).

FIG. 7 shows a schematic view of the retroperfusion system of FIG. 5further comprising a connection assembly.

FIG. 8 shows a side view of the retroperfusion system of FIG. 7 asapplied to a brain.

FIG. 9 shows a flow chart of a method for laparoscopically deliveringthe retroperfusion system of FIG. 7 to a targeted cerebral vein in orderto provide retroperfusion therapy thereto.

FIG. 10A shows a side view of at least one embodiment of a catheter fordelivering arterial blood within a venous vessel.

FIG. 10B shows a cross sectional view of the distal end of the catheterof FIG. 10A.

FIG. 11 shows a side view of a retroperfusion system for providing aretroperfusion therapy to an ischemic area of a brain.

FIG. 12 shows a flow chart of a method for percutaneously delivering theretroperfusion system of FIG. 11 to a targeted cerebral vein in order toprovide retroperfusion therapy thereto; and

FIG. 13 shows a block diagram of a regional hypothermia system and kitused in connection with an exemplary device or system of the presentdisclosure.

FIG. 14 shows representative experimental tracing obtained from thesubendocardial temperature probe showing regional decrease intemperature when retroperfusion was instituted, and later increase intemperature when retroperfusion was culminated (balloon deflation);

FIG. 15A shows ST-segment changes in response to the initial ischemicinsult (LAD occlusion) followed by treatment (SARP and MH-SARP) andreperfusion;

FIG. 15B shows arrhythmic events, namely the frequency of arrhythmicevents in the control, normothermia, and hypothermia groups during thereperfusion period, wherein * indicates a significance between controland normothermia groups and wherein † indicates significance betweencontrol and hypothermia groups;

FIG. 16 shows cardiac troponin (cTnI) levels over time in the control,normothermia, and hypothermia groups, wherein * indicates significancebetween control and normothermia groups, and wherein † indicatessignificance between control and hypothermia groups;

FIG. 17A shows the relative expression of miR-1/miR-16, and FIG. 17Bshows the miR-133a/miR-16 in the control, normothermia, and hypothermiagroups at baseline and 90 minutes, wherein * indicates significancebetween baseline and 90 minutes in the control group;

FIG. 18A shows the infarcted area (relative to the area at risk) in thecontrol, normothermia, and hypothermia groups, and FIG. 18B Myocardialsections from control (left), normothermia (central), and hypothermia(right) groups double-stained with Evans blue and TTC demarcating areaof infarction, wherein * indicates significance between control andnormothermia groups, and wherein † indicates significance betweencontrol and hypothermia groups.

FIGS. 19A, 19B, 19C, and 19D show representative histological samplesstained for the reperfusion injury marker caspase-3 (red) in healthyviable myocardium (FIG. 19A) and control (FIG. 19B), normothermia (FIG.19C) and hypothermia (FIG. 19D) groups.

FIGS. 20A, 20B, and 20C show indices of cardiac metabolism in responseto SARP and MH-SARP, with levation in effluent oxygen (FIG. 19A) duringretroperfusion supports conversion to anaerobic glycolysis and ischemicmetabolism as evidenced by increases in glucose uptake (FIG. 19B) andlactate release (FIG. 19C) across the treated myocardium, wherein *indicates significance between normothermia and control; wherein †indicates significance between hypothermia and control; wherein ‡indicates significance after 5 min of therapy in the normothermia andhypothermia groups relative to their baseline values; and wherein **indicates significance after 30 min of therapy in the normothermia andhypothermia groups relative to their baseline values.

DETAILED DESCRIPTION

Reference will now be made to the embodiments illustrated in thedrawings and specific language will be used to describe the same. Itwill nevertheless be understood that no limitation of scope is intendedby the description of these embodiments.

The devices, systems and methods described herein provide for a bridgetherapy that is capable of supplying a patient's own oxygenated arterialblood to the compromised penumbral region of the brain via cerebralpulsatile venous retroperfusion. In this manner, the devices, systemsand methods described herein facilitate the provision of oxygen-richblood to the penumbra and thereby extend the window during which thepenumbral cells remain viable. Extending the window of viability of thepenumbra allows for the use of several new therapies for the treatmentof stroke including, without limitation, the delivery of neuroprotectiveagents and thrombolytic drugs to the cerebral venous system as theagents and drugs will be allowed a sufficient period of time to becomepharmaceutically effective.

The normal human brain weighs about 1,500 grams and contains about 75milliliters of blood. Of the 75 milliliters of blood, only about ten(10) to twenty (20) milliliters is arterial. Accordingly, the vastmajority of the blood within the brain is venous blood (between aboutfifty-five (55) and about sixty (60) milliliters). This large amount ofvenous blood provides significant surface area for delivery andtransport of oxygen and other nutrients through the venous system.Furthermore, unlike the heart, the venous system of the brain is not asingle outlet system and contains many more vessels that are largelyinterconnected. This unique physiology facilitates the prevention ofedema during selective retroperfusion techniques.

At rest and normothermia, the brain of an awake subject typicallyreceives blood flow between about 45 to 60 milliliters per 100 grams ofbrain tissue per minute at a perfusion pressure of greater than about 70mmHg. Further, the maximum pressure that cerebral capillaries arenormally subjected to is about 30 mmHg with a mean of about 22 mmHg. Asa general consideration, under physiologic conditions capillarypressures beyond 25 mmHg can lead to complications such as tissue edema.Similarly, during a retrograde cerebral perfusion (“RCP”) procedure, itis conventionally recommended that the RCP pressure does not exceed 25mmHg. However, because RCP pressure is measured in the large veins, itdoes not accurately represent the pressure in the related capillarysystems. For example, a RCP pressure measuring 25 mmHG within the largeveins will be significantly lower in the related capillaries.Accordingly, the conventionally recommended RCP pressure of less than 25mmHg used in conventional RCP therapies is considered insufficient foropening up the cerebral microvessels and providing an adequate bloodsupply thereto. Furthermore, conventional RCP pressures are likely tocause maldistribution of blood throughout the brain due, at least inpart, to the sudden loss of cerebral perfusion pressure associated withconversion of antegrade to retrograde perfusion, which may lead to thecollapse of the cortical veins and an increased resistance to opening ofthe cerebrovenous vessels. For these reasons a retrograde perfusionpressure of greater than about 25 mmHg may not necessarily cause tissueedema and some clinical reports suggest that maintaining RCP atrelatively high perfusion pressures (e.g., greater than about 25 mmHg)appears to be safe, with evidence of good clinical outcomes and noevidence of either cerebral edema or hemorrhage. While the devices,systems and methods described herein subject the cerebral venous systemto such higher RCP pressures, characteristics of the devices, systemsand methods described herein provide safeguards against overloading thecerebral venous system.

Now referring to FIG. 1, a schematic view of a retroperfusion catheter10 is shown. As the various embodiments of the catheter 10 will bedescribed in connection with the provision of retrograde cerebralperfusion therapy to a brain, it will be understood that the catheter 10is not limited to use in connection with the brain and may be applied toany other areas of the body where the characteristics and/orconfiguration of the catheter 10 may be useful.

The catheter 10 is configured to be placed within a venous vessel andcomprises a flexible, elongated tube having a proximal end 12, a distalend 14, and a body 16 having a lumen 18. The catheter 10 may becomprised of any suitable material known in the medical arts and thedimensions of the catheter 10 may vary depending on the particulars ofthe specific patient or with respect to the vein to be cannulated. Forexample and without limitation, the catheter 10 may be configured forinsertion within the cerebral venous system to facilitate retrogradecerebral perfusion techniques. Furthermore, the catheter 10 may becoated with heparin or any other suitable anti-coagulant such that thecatheter 10 may be placed within a vessel for an extended period of timewithout inhibiting the blood flow therethrough due to coagulation.

As shown in FIG. 1, the catheter 10 may comprise a tapered configurationto facilitate advancement of the distal end 14 of the catheter 10 intothe venous capillaries of the cerebrum or any other narrow vessels asmay be appropriate. While one example of the tapered configuration ofthe catheter 10 is shown in FIG. 1, it will be appreciated that thecatheter 10 may be configured in any manner, tapered or otherwise, thatallows the distal end 14 of the catheter 10 to be advanced through ablood vessel having a decreasing diameter.

The proximal end 12 of the catheter 10 is open and in fluidcommunication with the lumen 18 of the body 16. The proximal end 12 ofthe catheter 10 may be configured in any fashion so long as arterialblood is allowed to flow therethrough and into the lumen 18 of thecatheter 10. For example, in the at least one embodiment shown in FIG.1, the proximal end 12 is configured as a female connector comprising aconnector ring 22. Similarly, the distal end 14 of the catheter 10 isconfigured to allow blood within the lumen 18 to flow out of thecatheter 10. Accordingly, when the catheter 10 is positioned within avenous vessel and supplied with arterial blood, the oxygenated arterialblood is allowed to flow into the catheter 10 through the proximal end12, through the lumen 18, and out of the catheter 10 through the distalend 14 (as well as through a plurality of orifices 20 which will bediscussed in further detail herein). As this is a retroperfusiontechnique, it will be understood that the arterial blood beingintroduced into the vein through the catheter 10 is flowing in adirection retrograde to the normal flow of venous blood.

The distal end 14 of the catheter 10 is further configured such that oneor more guidewires 40 positioned within the lumen 18 of the body 16 maybe advanced therethrough (see FIG. 2). In addition, the distal end 14further comprises one or more sensors 24. While the one or more sensors24 are described herein as being positioned on the distal end 14 of thecatheter 10, it will be appreciated that the one or more sensors 24 maybe positioned anywhere on the body 16 of the catheter 10.

Among other things, inclusion of the at least one sensor 24 on thecatheter 10 can provide information regarding the pressure within thevein into which the catheter 10 is being inserted. In this manner, theat least one sensor 24 can assist a clinician in determining theseverity of ischemic damage to an affected area of the brain, as well aswhether or not the appropriate pressure drop in the retroperfusedarterial blood flow has been achieved upon initiation of theretroperfusion therapy.

The one or more sensors 24 of the distal end 14 may comprise any sensorthat may be useful in the medical arts, such as and without limitation,sensors to measure the flow rate within the vein of interest, pressuresensors, and/or sensors for measuring the pH, the partial pressure ofcarbon dioxide within the vein or oxygen saturation, lactic acidconcentration, or temperature of the blood therein. The inclusion ofspecific type(s) of sensors 24 on the distal end 14 of the catheter 10may be determined on a case-by-case basis, depending on the particularneeds of the patient at issue. For example and without limitation, theat least one sensor 24 comprises a flow sensor to assist a clinicianwith tailoring the flow rate within the perfused vein to a specificvalue.

The at least one sensor 24 of the catheter 10 is further capable oftransmitting the data collected to an external device. As shown in FIG.1, one or more of the at least one sensors 24 may be a wired device. Inthe at least one embodiment shown in FIG. 1, the sensor 24 is coupledwith a sensor cable 26 for transmitting the data gathered by the relatedsensor 24 to a remote module 270 (see FIG. 4). The sensor cable 26extends through the lumen 18, out of the proximal end 12 of the catheter10, and is coupled with the remote module 270 that may either beimplanted on the patient subcutaneously or positioned remotely. In thismanner, the data gathered by each of the at least one sensors 24 can betransmitted through the sensor cable 26 to the remote module 270 suchthat a clinician can view and/or ascertain the same on a real-time basisor otherwise. Alternatively or additionally, one or more of the at leastone sensors 24 may be capable of wirelessly communicating the data ithas gathered to the remote module 270 through the use of telemetrytechnology, the internet, radio waves, or any other wireless means. Assuch, wireless sensors 24 do not require attachment to the sensor cable26 and can wirelessly transmit the gathered data to the remote module270 without being in physical or electrical contact therewith.

The body 16 of the catheter 10 extends between the proximal and distalends 12, 14 of the catheter 10 and comprises a plurality of orifices 20disposed along its length. Each of the plurality of orifices 20 are influid communication with the lumen 18 of the catheter 10 such that whenarterial blood flows through the lumen 18 of the catheter 10, a portionof the blood flows through the plurality of orifices 20 and into thecannulated vein. In this manner, the plurality of orifices 20 of thecatheter 10 facilitate the controlled introduction of the oxygen-richblood into the cerebral venous system.

The specific number, size and placement of the orifices 20 may bedetermined on a case-by-case basis according to the pressure and/or theflow rate desired within the cerebral venous system. For example andwithout limitation, if a higher flow rate is desired, the body 16 of thecatheter 20 may comprise numerous orifices 20 each having a largediameter. Alternatively, if a lower flow rate is desired, the body 16 ofthe catheter may not comprise as many orifices 20 and/or each of theplurality of orifices 20 may comprise a small diameter. In a similarfashion, the size, position and number of orifices 20 may also have anaffect on the pressure within the cerebral vein in which the catheter 10is inserted (i.e. the more arterial blood flow that is allowed to flowtherein, the higher the pressure within the vein and vice versa).

As shown in FIG. 1, the catheter 10 may further comprise one or moreexpandable balloons 30, 32 coupled with an intermediary portion of theexternal surface of the body 16 of the catheter 10 such that each of theexpandable balloons 30, 32 encases the catheter 10. In the at least oneembodiment of the catheter 10 illustrated in FIG. 1, a first expandableballoon 30 is coupled with the body 16 of the catheter 10 at a firstposition and a second expandable balloon 32 is coupled with the externalsurface of the body 16 of the catheter 10 at a second position. Thesecond expandable balloon 32 is positioned distally on the externalsurface of the body 16 of the catheter 10 relative to the firstexpandable balloon 30.

Each of the expandable balloons 30, 32 may comprise any expandableballoon that is appropriate for insertion within a vessel and maycomprise any material suitable for this function including, withoutlimitation, polyethylene, latex, polyestherurethane, polyurethane,silastic, silicone rubber or combinations thereof. In addition, the atleast one balloons 30, 32 may be coated with heparin or any othersuitable anti-coagulant such that the at least one expandable balloon30, 32 may be placed within a vessel without the risk of coagulation.The size and configuration of each expandable balloon will differbetween patients and applications. In operation, the at least oneexpandable balloon 30, 32 can be used to intermittently occlude the veinand prevent the antegrade flow of blood therethrough and anchor thecatheter 10 in the desired position within a vessel wall.

The interiors of each of the at least one expandable balloons 30, 32 arein fluid communication with the lumen 18 of the catheter 10. While itwill be appreciated that this can be achieved using various differentmeans such as valves, openings or other conduits, in the embodimentshown in FIG. 1, each of the balloons 30, 32 is positioned on the body16 of the catheter 10 at a location over one or more pores 34 thattraverse the external surface of the body 16 and are in fluidcommunication with the lumen 18 of the catheter 10. Accordingly, asarterial blood flows through the lumen of the catheter, a portionthereof necessarily flows into the interior of each of at least oneexpandable balloons 30, 32 through the related pores 34. In this manner,each of the balloons 30, 32 is capable of automatically moving from adeflated to an expanded position when blood flows through the lumen 18of the catheter 10. Likewise, each of the balloons 30, 32 is furthercapable of automatically moving from the expanded position back to adeflated position when the arterial blood flow through the lumen 18 ofthe catheter 10 either is not sufficient to maintain the balloons 30, 32in the expanded position or ceases altogether. In both of these cases,when the pressure is not sufficient to maintain the arterial bloodwithin the interior of the at least one balloon 30, 32, the arterialblood drains back through the at least one pore 34 in the body 16 of thecatheter 10 and into the lumen 18 in accordance with the antegrade flowof blood through the venous vessel.

With respect to use of the catheter 10 to provide retrograde cerebralperfusion therapy for treatment of a stroke or otherwise, the proximalend 12 of the catheter 10 is coupled with an arterial blood supply (aswill be described in further detail herein) such that the arterial bloodis injected into the lumen 18 of the catheter 10 through the proximalend 12 thereof in synchrony with the patient's sinus rhythm.Accordingly, when oxygen-rich arterial blood is pumped in a retrogradefashion into a venous vessel as a result of the systolic contraction ofthe heart, the expandable balloons 30, 32 of the catheter 10 each expandas the arterial blood flows into the interiors thereof. As theexpandable balloons 30, 32 are positioned at different locations alongthe body 16 of the catheter 10, the first balloon 30 may expand prior tothe second balloon 32 depending on the flow rate and pressure of thearterial blood flow moving through the lumen 18 of the catheter 10.

The expansion of the expandable balloons 30, 32 occludes the venousvessel in which the catheter 10 is inserted, prevents the normalantegrade flow of blood through the venous vessel, and increases thepressure therein. In this manner, the oxygen-rich arterial blood thatwas delivered into the vessel through the plurality of orifices 20 andthe distal end 14 of the catheter 10 at a location upstream of theballoon occlusions is forced to remain within the vein for a period oftime and perfuse the surrounding capillaries. Accordingly, the occlusionof the vein by the at least one expanded balloon 30, 32 allows thepenumbral tissue vascularized by the venous vessel at issue to benefitfrom the nutrients contained in the arterial blood.

Thereafter, during diastole when the arterial blood is not activelypumped by the heart through the catheter 10, the arterial blood pumpedinto the catheter 10 (and thus the interiors of the balloons 30, 32) inthe previous systolic cycle drains back into the lumen 18 of thecatheter 10 through the one or more pores 34. This immediately reducesthe pressure within the interiors of the balloons 30, 32 andautomatically deflates the same. Due to the placement of the balloons30, 32 on the body 16 of the catheter 10, the second balloon 32 maydeflate or begin deflating before the first balloon 30 due to the flowof arterial blood through the catheter 10 (i.e. in succession). (It willbe appreciated that the first and second balloons 30, 32 mayexpand/deflate in succession or in unison, depending on the forwardpressure of the system). In this manner, the expandable balloons 30, 32no longer occlude the vein and the antegrade flow of blood through thevenous vessel resumes. Accordingly, the venous blood and thesupplemented arterial blood within the vein is allowed to drain out ofthe venous vessel in accordance with normal antegrade flow and thepressure within the venous vessel is reduced.

The rate at which the expandable balloons 30, 32 of the catheter 10automatically move between the expanded and deflated positions can bemanipulated pursuant to each of the balloons' 30, 32 pressure to volumeratio and/or the size and number of pores 34 associated therewith. Forexample, and without limitation, a clinician can manipulate theconfiguration of either or both of the expandable balloons 30, 32 (i.e.the thickness and/or elasticity of the material comprising theexpandable balloons 30, 32 and/or the overall shape and size thereof) toachieve the desired pressure to volume ratio. In this manner, theexpandable balloons 30, 32 are capable of automatically expanding at adesired rate and to a desired size when a sufficient pressure is exertedwithin their interiors by the influx of arterial blood. In addition, theexpandable balloons 30, 32 are also capable of automatically deflatingat a desired rate when the pressure within the interiors of the balloons30, 32 falls below a predetermined threshold due to the outflow ofarterial blood.

As previously indicated, the configuration of the one or more pores 34may also be modified to achieve a specific expansion and/or deflationrate. For example, the size and/or number of the pore(s) 34 can beincreased if a faster expansion and/or deflation rate is desired, or thepore(s) 34 may be decreased in size and/or number for a slower, morecontrolled expansion and/or deflation rate. In this manner, a cliniciancan ensure that the expandable balloons 30, 32 will expand to theappropriate size and deflate therefrom within a desired timeframe andtherefore achieve the desired effect.

Now referring to FIG. 3, a side view of at least one alternativeembodiment of the catheter 10 is shown. In this at least one embodiment,the catheter 10 further comprises a sheath 150. The sheath 150 isconfigured to be placed within a venous vessel over the catheter 10 andcomprises a semi-flexible, elongated tube having a proximal end (notshown), a distal end 154 and a lumen configured to slidably receive thebody 16 of the catheter 10 therein. The sheath 150 may be comprised ofany suitable material including, without limitation, polyurethane,poly(tetrafluoroethylene) or silicone rubber. Furthermore, the sheath150 may be coated with heparin or any other suitable anti-coagulant suchthat the sheath 150 may be placed within a vessel without inhibitingblood flow due to coagulation.

The dimensions of the sheath 150 may vary depending on the particularsof a specific patient or with respect to the vein to be cannulated, andare directly related to the dimensions of the catheter 10. For example,the diameter of the sheath 150 is such that while the lumen of thesheath 150 is capable of slidably receiving the body 116 of the catheter110 therein, the sheath 150 is tightly fit around the body 116 of thecatheter 10 when the sheath 150 is advanced there over. In this manner,when the sheath 150 is advanced over a portion of the body 116 of thecatheter 10, the sheath 150 effectively seals the orifices 120 of thecatheter 10 that are positioned there under. In addition, the sheath 150is also capable of being advanced over the at least one expandableballoons 130, 132 located at various positions on the body 116 of thecatheter 10 when the expandable balloons 130, 132 are in the deflatedconfiguration. Accordingly, a clinician can customize the flow of bloodinto the venous vessel from within the lumen 118 of the catheter 10 byadvancing or retracting the sheath 150 to either increase or decrease,respectively, the amount of orifices 120 that are available to allowblood to flow therethrough. In addition, by advancing the sheath 150over one or more of the at least one balloons 130, 132, a clinician candecrease the number of expandable balloons available to occlude the veinduring systole and thereby promote the blood within a particular area ofthe vein to drain therefrom.

Due to the inherent pressure differences between the arterial and venoussystems, one of the main challenges of successfully deliveringretroperfusion therapies is that the arterial blood pressure must bereduced prior to being introduced into a vein due to the thinner andmore fragile anatomy of the venous walls. Indeed, subjecting a venousvessel to the high pressures of arterial blood flow typically results inrupture of the venous wall. Accordingly, with retroperfusion therapies,it is critical to ensure that the pressure of the arterial blood flow isat least initially controlled such that the venous vessel is notsubjected to the unregulated pressure of the arterial blood flow.

Maintaining control of this pressure discrepancy is especially importantwhen retroperfusion therapy is applied to the venous system of a brain.The tight normal range of the brain's intracranial pressure is due, atleast in part, to its enclosure within the cranium. Accordingly, evenslight deviations in the normal pressure within the brain's venousvessels can result in extremely problematic outcomes. Accordingly, inaddition to regulating the amount of blood flow into the ischemic areaof the brain, it is also necessary to regulate the pressure of thearterial blood prior to its introduction into the venous system throughthe catheter 10.

Now referring to FIGS. 4 and 5, side views of an autoretroperfusionsystem 200 are shown. With respect to the brain, the autoretroperfusionsystem 200 may be used in the treatment of stroke and, specifically, asa bridge therapy to extend the viability of the penumbra region of theischemic brain tissue. As previously described with respect to thecatheter 10, the autoretroperfusion system 200 is capable of providingarterial blood flow to an ischemic region of a patient's brain byinjecting arterial blood in a controlled manner in synchrony with thepatient's sinus rhythm. Furthermore, the autoretroperfusion system 200is capable of controlling the pressure of the arterial blood flow priorto introducing the same to the venous system of the brain such that whenthe arterial blood flow is first introduced to the vein, the pressure ofthe re-routed arterial blood flow is already reduced such that thethinner venous vessels are protected and the blood pressure is maintainwithin an acceptable pressure range.

As illustrated in FIG. 5, the autoretroperfusion system 200 comprisesthe catheter 10, a flow unit 210, and a source of arterial blood flow250. The catheter 10 is for placement within the venous vessel of thebrain and is configured as previously described in connection with FIGS.1-3. The flow unit 210 is configured for use in connection with thecatheter 10 and is responsible for regulating the arterial bloodpressure prior to its introduction into the catheter 10. The source ofarterial blood flow 250 is for placement within an arterial vessel andis configured to re-route at least a portion of the arterial blood flowwithin the arterial vessel into the autoretroperfusion system 200 andmay comprise a catheter or other device as is known in the art.

The flow unit 210 of the autoretroperfusion system 200 is responsible,at least in part, for the regulation of the pressure of the arterialblood flow prior to its introduction into the catheter 10 and ultimatelythe vein. The flow unit 210 comprises a proximal end 212, a distal end214, a body 216 extending between the proximal and distal ends 212, 214,a chamber 220, and an interior 218 extending through the chamber 220 andbetween the proximal and distal ends 212, 214 of the flow unit 210. Boththe proximal end 212 and the distal end 214 of the flow unit 210 maycomprise any standard catheter materials that are suitable in themedical arts. The proximal end 212 of the flow unit 210 is configured toreceive fluid therethrough and to allow such fluid to flow into theinterior 218 of the flow unit 210. In addition, the proximal end 212 isconfigured to securely couple with the source of arterial blood flow250. The source of arterial blood flow 250 and the proximal end 212 maybe coupled in any manner known in the art, provided a secure connectionis formed therebetween and arterial blood is allowed to travel from thesource of arterial blood flow 250 into the interior 218 of the flow unit210 through the proximal end 212 thereof.

The distal end 214 of the flow unit 210 comprises an open end and isconfigured such that arterial blood can flow therethrough. In addition,the distal end 214 of the flow unit 210 is configured to securely couplewith the proximal end 12 of the catheter 10. For example and withoutlimitation, the distal end 214 of the flow unit 210 may comprise a maleconnector having a connector ring 222 such that the distal end 214 ofthe flow unit 210 can securely mate with the female configuration andconnector ring 22 of the proximal end 12 of the catheter 10 (see FIG.4). When the flow unit 210 is coupled with the source of arterial bloodflow 250 and the catheter 10, the arterial blood is allowed to flow intothe flow unit 210 through the proximal end 212 thereof, through theinterior 218 of the flow unit, and into the lumen 18 of the catheter 10through the distal end 214 of the flow unit 210.

As shown in FIG. 4, the distal end 214 of the flow unit 210 may furthercomprise at least one sensor 224 disposed therein. The at least onesensor 224 may be disposed in any location within the distal end 214 ofthe flow unit 210 so long as the at least one sensor 224 is capable ofgathering data on the flow of fluid traveling therethrough. As shown inFIG. 4, in at least one embodiment, the at least one sensor 224 may bedisposed on the interior wall of the distal end 214 and/or be tetheredto the interior wall of the distal end 214 such that the at least onesensor 224 is floating within the arterial blood flowing through theinterior 218 of the flow unit 210.

The at least one sensor 224 may be used for monitoring purposes and iscapable of periodically or continuously collecting data from thearterial blood flowing through the interior 218 of the flow unit 210.For example, the at least one sensor 224 may be capable of monitoringthe pressure and/or flow rate of the arterial blood flowing through thedistal end 214 of the flow unit 210. Additionally, one or more of the atleast one sensors 224 may be used to monitor the pH or theconcentrations of carbon dioxide, lactate or other compounds within thearterial blood, activating clotting time data, or any other data on thearterial blood that may be useful. The inclusion of specific type(s) ofsensors 224 in the distal end 214 of the flow unit 210 may be determinedon a case-by-case basis, depending on the particular needs of thepatient.

The at least one sensor 224 of the distal end 214 of the flow unit 210is further capable of transmitting the data collected to an externaldevice. In the at least one embodiment shown in FIG. 4, the at least onesensor 224 is a wired device. In this embodiment, the wire component ofthe sensor travels through a sensory port 225 to a remote module 270(which will be described in more detail herein). In this at least oneembodiment, the sensory port 225 is configured as an elongated conduitin which the wire of the at least one sensor 224 is encased.Alternatively or additionally, one or more of the at least one sensors224 may be capable of wirelessly communicating the data it has gatheredto the remote module 270 through the use of telemetry technology, theinternet, radio waves, or other wireless means, such that the collecteddata can be easily accessed by a clinician on a real-time basis orotherwise. It will be understood that the flow unit 210 may comprise anynumber or type of sensors 224 and that each of the at least one sensors224 may be capable of collecting a specific type or multiple types ofdata from the arterial blood flowing through the flow unit 210.

The chamber 220 of the flow unit 210 is coupled with the exteriorsurface of the body 216 of the flow unit 210 and comprises an interior232 and an exterior cage or surface comprised of any material that iscapable of being inflated and deflated. For example and withoutlimitation, in at least one embodiment, the chamber 220 may comprisepolyethylene, latex, polyestherurethane, polyurethane, silastic,silicone rubber or combinations thereof. In operation, the chamber 220can be used to form a temporary stenosis or barrier within the interior218 of the flow unit 210 in order to reduce the pressure of arterialblood flowing therethrough.

The chamber 220 is capable of being controlled by a clinician, throughuse of the remote module 270 or otherwise, such that the chamber 220 caninflate and/or deflate to the appropriate size based on the pressureand/or flow rate of the arterial blood flowing through the interior 218of the flow unit 210. The interior 232 of the chamber 220 is in fluidcommunication with a fluid source 280 through at least one port 230.Accordingly, the at least one port 230 functions as a conduit throughwhich a fluid supplied from the fluid source 280 (e.g., a gas or aliquid) can be injected into or removed from the interior 232 of thechamber 220. The fluid source 280 may be positioned externally of thepatient or may comprise a subcutaneous port through which fluid can beperiodically injected and withdrawn.

As shown in FIGS. 4, 5, 6A, and 6B, a portion of the body 216 of theflow unit 210 traverses the center of the chamber 220. As this portionis surrounded by the chamber 220, the external surface of the portion ofthe body 216 surrounded by the chamber 220 may be in contact any liquidor gas injected into the interior 232 of the chamber 220 and theinternal surface of the portion of the body 216 surrounded by thechamber 220 may be in contact with blood flowing through the interior218 of the flow unit 210.

The portion of the body 216 surrounded by the chamber 220 is comprisedof a flexible or semi-flexible membrane such that the chamber 220 actsas a diaphragm with respect to the body 216, and thus the interior 218,of the flow unit 210. In other words, when the pressure within theinterior 232 of the chamber 220 is greater than the pressure within theinterior 218 of the flow unit 210 due to the injection of fluid thereinor otherwise, the chamber 220 asserts a compressing force on theflexible or semi-flexible walls of the portion of body 216 of the flowunit 210 that is sufficient to decrease the diameter of the underlyinginterior 218 of the flow unit 210 (see FIG. 6A). In this manner, thechamber 220 is capable of decreasing the size of the interior 218 of theflow unit 210 and thus forming a stenosis therein such that the flow ofarterial blood therethrough is inhibited. Conversely, when the pressurewithin the interior 232 of the chamber 220 is less than the pressurewithin the interior 218 of the flow unit 210, the body 216 of the flowunit 210 is maintained at its standard diameter and the size of thechamber 220 is unaffected (see FIG. 6B).

By controlling the volume of fluid within the interior 232 of thechamber 220 as a function of time, the flow unit 210 can affect the wavepressure and volume of arterial blood flowing through the interior 218of the flow unit 210 and out of the distal end 214 thereof into thecatheter 10. For example and without limitation, in at least oneembodiment, the flow unit 210 is capable of decreasing the pressure andvolume of arterial blood flowing through the distal end 214 of the flowunit 218 when a sufficient volume of fluid, such as for example, carbondioxide, is injected into the interior 232 of the chamber 220 throughthe at least one port 230. When this occurs, a compressional force isexerted on the portion of the body 216 of the flow unit 210 surroundedthereby such that a temporary stenosis is formed within the underlyinginterior 218 of the flow unit 210. As the arterial blood flows throughthe stenosed interior 218 of the flow unit 210, the volume of arterialblood allowed therethrough is necessarily decreased along with thepressure of the arterial blood flowing through the distal end 214 of theflow unit 210. In this manner, the flow unit 210 can achieve the desiredpressure drop in the arterial blood flowing between the arterial andvenous systems. Furthermore, the stenosis effect of the chamber 220 canbe reversed by removing the carbon dioxide or other fluid from theinterior 232 of the chamber 220 through the at least one port 230. Inthis manner, the portion of the interior 218 surrounded by the chamber220 can return to its original configuration.

Because the venous system of the brain is so sensitive to changes inpressure and flow, it is necessary to counteract the increased arterialflow rate resulting from the arterial blood moving through the stenosisformed by the chamber 220. Accordingly, the autoretroperfusion system200 is capable of varying the inflation and deflation of the chamber 220(and therefore the creation and removal of the stenosis effect on theinterior 218 of the flow unit 210) as a function of time. For exampleand without limitation, the volume of the interior 232 of the chamber220 may be manipulated so as to drive the pressure of the arterial bloodflowing through the interior 218 of the flow unit 210 to between about30 mmHg and about 40 mmHg for a predetermined period of time.Thereafter, the volume of the interior 232 of the chamber 220 may bemanipulated such that the pressure of the arterial blood flowing throughthe interior 218 of the flow unit 210 drops for a predetermined periodof time.

Through periodically driving the pressure and/or flow rate of thearterial blood to a higher pressure and thereafter decreasing the same,the autoretroperfusion system 200 can ensure that any stress caused tothe venous system by the retrograde arterial blood flow is periodicallyand consistently relieved, thereby providing the venous system atemporary reprieve to prevent overload. It will further be understoodthat this periodic manipulation of the arterial blood flow and pressurethrough use of the flow unit 210 may also be coordinated with the sinusrhythm of the patient. In this manner, not only is the venous systemallowed a periodic interruption to the increased pressure and flow rateof the arterial blood, but antegrade blood flow through the venoussystem may also be allowed to periodically resume, thereby furtherreducing the overall stress on the system.

The rate at which the chamber 220 of the flow unit 210 is inflated anddeflated may be controlled by a remote module 270. The remote module 270comprises a computer or other processing means, and is capable ofreceiving the data collected by the sensors 24, 224 of theautoretroperfusion system 200 and causing fluid to be injected into orwithdrawn from the interior 232 of the chamber 220. As previouslydescribed, the remote module 270 may be coupled with the at least onesensor 224 of the distal end 214 of the flow unit 210 via a wire encasedin the sensory port 225 (as shown in FIG. 4) and/or be capable ofreceiving the data collected from the at least one sensor 224 viawireless transmission. Similarly, the remote module 270 may be coupledwith the at least one sensor 24 of the catheter 10 and/or be capable ofreceiving the data collected from the at least one sensor 24 viawireless transmission. Furthermore, as the remote module 270 may bepositioned remotely from the patient, the data gathered by the sensors24, 224 of the autoretroperfusion system 200 is easily accessible by aclinician.

The remote module 270 is further coupled with the fluid source 280 andis capable of controlling the amount of fluid injected into andwithdrawn from the interior 232 of the chamber 220, as well as theintervals at which the same occurs. As previously described, the volumeof fluid within the interior 232 of the chamber 220 has a direct affecton the rate and pressure of the arterial blood flowing through thedistal end 214 of the flow unit 210. Accordingly, the remote module 270can control the pressure drop in the arterial blood through manipulationof the fluid volume within the interior 232 of the chamber 220.

In addition, the remote module 270 is configured such that it can beprogrammed to automatically analyze the data received from the sensors24, 224 of the autoretroperfusion system 200 and, based on the resultsthereof, automatically adjust the volume of fluid injected into orwithdrawn from the interior 232 of the chamber 220 in order maintain thearterial blood pressure and flow rate within the acceptablepre-programmed parameters. Accordingly, due to the placement of the atleast one sensors 24, 224 of the autoretroperfusion system 200, theremote module 270 can quickly calculate the effect that variousmanipulations of the volume of fluid within the interior 232 of thechamber 220 are having on the flow and pressure of the arterial bloodperfusing the venous vessel, and maintain real-time data on the overalleffect the retroperfusion therapy is having on the venous system.

In at least one embodiment, the remote module 270 can be driven by analgorithm such that the remote module 270 is capable of executing theinflation and deflation of the chamber 220 of the flow unit 210 pursuantto a set of desired flow parameters, pressure and perfusion rates. Inother words, in this at least one embodiment, the remote module 270utilizes an algorithm to ascertain the optimal flow parameters withinthe venous vessel based on the data collected from the sensors 24, 224.Thereafter, based upon those parameters, the remote module 270automatically manipulates the injection of fluid into and the withdrawalof fluid from the interior 232 of the chamber 220 on an interval basisto achieve the arterial blood flow, pressure, and any other criterion ofinterest within the optimal ranges.

As previously discussed, the remote module 270 can be programmed toperform these functions at reoccurring intervals in order to ensure thatthe venous system is not being overstressed. For example, in at leastone embodiment, the remote module 270 may be programmed to repeat thecycles of maintaining the pressure of the arterial blood flow flowingthrough the distal end 214 of the flow unit 210 to between about 30 andabout 40 mmHg for 5 seconds, followed by an interval of decreasedpressure in the arterial blood flow between about 20 to about 25 mmHgfor about 5 seconds. In addition, because the remote module 270 iscontinuously receiving data from the at least one sensors 24, 224 of theautoretroperfusion system 200, the remote module 270 can automaticallyadjust the fluid volume within the interior 232 of the chamber 230 toensure the proper pressure, flow rate and/or other parameters ofinterest are within acceptable levels.

In at least one embodiment of the autoretroperfusion system 200, thecomponents of the system 200 are available in a package. Here, thepackage may also contain devices to facilitate delivery of theautoretroperfusion system 200 such as venous and arterial accessdevices, a delivery catheter, one or more guidewires 40, or any otherdevices or materials that may be required to administer theautoretroperfusion system 200 appropriately.

Now referring to FIG. 7, a schematic view of an autoretroperfusionsystem 300 is shown. With respect to the brain, the autoretroperfusionsystem 300 may be used in the treatment of a stoke and, specifically, asa bridge therapy to extend the viability of the penumbra region of theischemic brain tissue. As previously described with respect to thecatheter 10, the flow unit 210, and the autoretroperfusion system 200,the autoretroperfusion system 300 is capable of providing arterial bloodflow to an ischemic region of a patient's brain by injecting arterialblood in a controlled manner in synchrony with the patient's sinusrhythm. Furthermore, the autoretroperfusion system 300 is capable ofcontrolling the pressure of the arterial blood flow as it enters thevenous vessel of the brain such that when the arterial blood flow isfirst introduced to the venous system, the pressure of the re-routedarterial blood flow is reduced to protect the thinner venous vessels andmaintain the same within an acceptable pressure range. In addition, theautoretroperfusion system 300 is capable of providing a sterileenvironment for the initial implantation and connection of theunderlying components of the autoretroperfusion system 300 and providesa mechanism for reducing the risk of air embolism resulting from theprocedure.

As illustrated in FIG. 7, the autoretroperfusion system 300 comprisesthe catheter 10, the flow unit 210, the source of arterial blood flow250, and a connection assembly 310. The catheter 10 is for placementwithin the venous vessel of the brain and is configured as previouslydescribed in connection with FIGS. 1-3. The flow unit 210 is likewisefor coupling the source of arterial blood flow 250 with the catheter 10and is responsible for regulating the arterial blood flow and pressureprior to its introduction into the catheter 10, and is configured aspreviously described in connection with FIGS. 4-6B. The source ofarterial blood flow 250 is for placement within an arterial vessel andis configured previously described in connection with theautoretroperfusion system 200. Finally, the connection assembly 310 isfor providing a sterile environment within which to connect thecomponents of the system 300 and to ensure that no harmful particulatesor gases contaminate the arterial blood flow being perfused into thevein of interest.

The connection assembly 310 comprises a corrugated, sterile bag that iscapable of securely coupling with both the distal end 214 of the flowunit 210 and the proximal end 12 of the catheter 10. In at least oneembodiment, the connection assembly 310 may be comprised of atransparent plastic material; however, it will be appreciated that theconnection assembly 310 may be formed of any flexible or semi-flexiblematerial that is capable of maintaining a sterile environment andcoupling with both the flow unit 210 and the catheter 10 in a mannersuch as to facilitate the flow of fluid therebetween.

The connection assembly 310 comprises a proximal end 312, a distal end314, a body 316 extending between the proximal and distal ends 312, 314,and a limb component 318 extending from the body 316. Both the body 316and the limb component 318 of the connection assembly 310 furthercomprise interiors 320, 322, respectively, and the interior 320 of thebody 316 is in fluid communication with the interior 322 of the limbcomponent 318. The limb component 318 of the connection assembly 310extends from the body 316 of the connection assembly 310 as shown inFIG. 6, and the interior 322 thereof is configured to slidably receivethe one or more guidewires 40 that may be used to facilitate advancementand placement of the distal end 14 of the catheter 10.

In addition to the aforementioned, the connection assembly 310 furthercomprises at least one flushing port 330 and at least one drainage valve332. The at least one flushing port 330 may be positioned in anylocation on the connection assembly 310 and is in fluid communicationwith the interior 320 of the body 316 of the connection assembly 310.Further, the at least one flushing port 330 is additionally coupled witha gas supply (not shown) such that a gas may be injected through the atleast one flushing port 330 and into the interior 320 of the connectionassembly 310. For example, and without limitation, the at least oneflushing port 330 may be coupled with a gas supply containing carbondioxide.

Furthermore, the at least one flushing port 330 can be used in variouscapacities in connection with the autoretroperfusion system 300. Forexample, and without limitation, upon placement of the system 300 withina body, the interiors 320, 322 of the body 316 and limb component 318 ofthe connection assembly 310 may be continuously flushed with an asepticgas to create a clean environment. In this manner, the proximal end 12of the catheter 10 and the distal end 214 of the flow unit 210 may beconnected within the aseptic interior 320 of the connection assembly310, thereby reducing the risk of introducing harmful microbes or othermatter into the venous system of the brain as a result of implanting thecatheter 10 therein. Moreover, using a resorbable gas, such as carbondioxide, to flush the system 300 can also provide the added benefit ofreducing the risk of air bubbles from entering the system and producingan air embolism.

The at least one drainage valve 332 comprises any one-way valve known inthe art and is in fluid communication with at least the interior 320 ofthe body 316. As shown in FIG. 7, the at least one drainage valve 332may also be in fluid communication with the interior 322 of the limbcomponent 318. The at least one drainage valve 332 of theautoretroperfusion system 300 automatically allows for any excess gasthat is injected into the system 300 through the at least one flushingport 330 or otherwise to be drained therefrom in a sterile andnoninvasive manner. As described in the at least one example where anaseptic gas is pumped into the system 300 through the at least oneflushing port 330 to provide a sterile environment in which the flowunit 210 and the catheter 10 may be connected, when the pressure withinthe interior 320, 322 of the connector assembly 310 begins to increasedue to the presence of the aseptic gas therein, the excess gas isautomatically drained through the at least one drainage valve 332 suchthat the gas added through the at least one flushing port 330 does notaffect the overall pressure of the system 300. The at least one drainagevalve 332 may be located outside of the body such that the excess gasdrains directly into the environment or, when the connection assembly310 is implanted at a location within the patient's body, the excess gascan drain from the at least one drainage valve 332 into a conduit thatroutes the gas to the external environment.

In operation, the connection assembly 310 is fitted over the distal end214 of the flow unit 210 and the proximal end 12 of the catheter 10 andforms a leak-free attachment with both components 10, 210. In the atleast one embodiment where the catheter 10 has been advanced over atleast one guidewire 40 to facilitate the proper placement of the distalend 14 thereof, the proximal end of the at least one guidewire 40 may bethreaded through the distal end 314 and limb component 318 of theconnection assembly 310 such that the at least one guidewire 40 can bemanipulated by a clinician with the connection assembly 310 securely inplace. Furthermore, prior to coupling the distal end 214 of the flowunit 210 and the proximal end 12 of the catheter 10 to allow thearterial blood to flow therethrough, the at least one flushing port 330may be used to infuse the interior 320 of the connection assembly 310with a gas to ensure a sterile environment and any excess gas can bedrained through the at least one drainage valve 322. In this manner, theconnection assembly 310 is capable of supplying an aseptic and air-freeenvironment in which the flow unit 210 and the catheter 10 may besecurely connected, thereby reducing the risk of air embolism orcontamination resulting from the procedure.

In at least one embodiment of the autoretroperfusion system 300, thecomponents of the system 300 are available in a package. Here, thepackage may also contain devices to facilitate delivery of theautoretroperfusion system 300 such as venous and arterial accessdevices, a delivery catheter, one or more guidewires 40, or any otherdevices or materials that may be required to administer theautoretroperfusion system 300 appropriately.

Now referring to FIG. 8, a side view of the retroperfusion system 300 isshown applied to the brain 400 of a patient in order to facilitate thetreatment of a stroke. In addition, FIG. 9 shows a flow chart of amethod 500 for performing automatic retroperfusion on a brain using theautoretroperfusion system 300. For ease of understanding, the steps ofthe method 500 described herein will be discussed relative to thecomponents of the retroperfusion system 300, but it will be appreciatedby one skilled in the art that any similar devices and/or systems can beused to perform this method 500. In addition, while the retroperfusionsystem 300 and the method 500 are described in connection with treatingan ischemic area of a brain through catheterization of a venous vesselextending into a penumbral area of a brain, it will be understood thatthe retroperfusion systems 200, 300 and the method 500 described hereinmay be applied to perform autoretroperfusion on any organ or tissue inneed of retroperfusion treatment.

In at least one approach to the method 500, at step 502, a topographicimage of the ischemic area of the brain 400, including the core ischemicinfarct 402 and the ischemic penumbra 404, is created using conventionalimaging techniques such as magnetic resonance imaging and/or x-raycomputer tomography. In this manner, a clinician can determine thelocation of the ischemic infarct 402 and the penumbra 404 based oncerebral blood flow characteristics and the blood volume within thedifferent areas of the brain 400. At step 504 an artery of interest (notshown) is percutaneously punctured under local anesthesia with aconventional artery access device or as otherwise known in the art. Forexample and without limitation, in at least one embodiment, an 18 gaugeneedle is inserted into the desired artery and the source of arterialblood flow 250 is positioned within the artery such that a portion ofarterial blood is re-routed therethrough, driven by the pulsatile rhythmof the beating heart. Here, the desired artery may comprise the femoralartery, the subclavian artery, the brachial artery, the radial artery,or any other artery that may be appropriate with respect to theparticular patient and/or application.

At step 506, a vein of interest 406 is percutaneously punctured underlocal anesthesia with a conventional venous access device or asotherwise known in the art. For example and without limitation, in atleast one embodiment, an 18 gauge needle is inserted into the jugularvein (labeled as vein 406 in FIG. 9). It will also be appreciated thatany other vein may be utilized, provided the vein facilitatesretroperfusion of the arterial blood to the desired area of the body.After the vein 406 has been punctured, at step 508, a soft guidewire 40is inserted into the opening in the vein 406 and advanced into thepenumbra region 404 of the brain 400. This may be facilitated throughuse of the brain topographic imaging taken at step 502 and/or throughx-ray (i.e. fluoroscopy) or other suitable visualization techniques.

After the distal end of the guidewire 40 is positioned in the desiredlocation within the penumbra 404 of the brain 400, the distal end 14 ofthe catheter 10 is inserted into the vein 406 following the guidewire 40at step 510. Specifically, the distal end 14 of the catheter 10 isthreaded over the guidewire 40, inserted into the vein 406 and advancedalong the main venous system to the target area within the penumbra 404.Step 510 may be performed under fluoroscopic control or with the aide ofother visualization techniques known in the art. Thereafter, theguidewire 40 may optionally be withdrawn from the body through the lumen18 of the catheter 10 at step 512.

At step 514, the connection assembly 310 is coupled with the proximalend 12 of the catheter 10 and the distal end 214 of the flow unit 210(see FIG. 7). The connection assembly 310 is fitted over the distal end214 of the flow unit 210 and the proximal end 12 of the catheter 10 andforms a leak-free attachment with both components 10, 210. Furthermore,in the at least one embodiment of the method 500 where the at least oneguidewire 40 was not withdrawn from the patient's body at step 512, theproximal end of the at least one guidewire 40 is threaded through thedistal end 314 and the limb component 318 of the connection assembly 310such that the at least one guidewire 40 extends through the interior 322of the limb component 318 as illustrated in FIGS. 7 and 8.

At step 516, the flow unit 210 is coupled with the source of arterialblood flow 250 and begins to receive arterial blood flow from thepunctured artery within the interior 218 thereof. In this manner, thearterial blood re-routed from the artery of interest (not shown) by thesource of arterial blood flow 250 is allowed to flow through the sourceof arterial blood flow 250 and into the proximal end 212 of the flowunit 210 in a pulsatile fashion pursuant to the rhythm of the patient'sheartbeat.

After the proximal end 12 of the catheter 10 and the distal end 214 ofthe flow unit 210 are positioned within the interior 320 of theconnection assembly 310 at step 514, at step 518 the connection assembly310 initiates the injection of gas into the interiors 320, 322 of thebody 316 and the limb component 318. Specifically, the clinician mayfacilitate the injection of a sterile gas into the interiors 320, 322 ofthe connection assembly 310 through the at least one flushing port 330such that the interiors 320, 322 are continuously flushed with thesterile gas. Concurrently, the excess gas injected into the interiors320, 322 is automatically drained from the connection assembly 310through the at least one drainage valve 332 of the connection assembly310. In addition, at step 518, if the at least one guidewire 40 has notpreviously been withdrawn from the patient's body through the lumen 18of the catheter 10 at step 512, the at least one guidewire 40 is nowremoved from the patient through the limb component 318 of theconnection assembly 310.

In at least one embodiment of the method 500, the gas injected into theinteriors 320, 322 of the connection assembly 310 comprises carbondioxide. The use of carbon dioxide to flush the autoretroperfusionsystem 300 ensures that the environment within the connection assembly310 is aseptic and free of contaminants and/or air bubbles. In thismanner, the coupling of the proximal end 12 of the catheter 10 with thedistal end 214 of the flow unit 210 can occur within an aseptic, sterileenvironment, under continuously flowing carbon dioxide (or other gas),and further reduce the risk of adding air to the vein 406 during theconnection of the components 10, 210. Accordingly, the sterileenvironment greatly reduces the risk that any harmful microbes or othermatter will be introduced into the venous system of the brain as well asthe risk of producing an air embolism within the vein 406 as a result ofthe therapy applied by the autoretroperfusion system 300.

At step 520, the distal end 214 of the flow unit 210 and the proximalend 12 of the catheter 10 are securely coupled with one another as shownin FIG. 8. Accordingly, the arterial blood from the artery of interest(not shown) is pumped in synchrony with the patient's sinus rhythmthrough the source of arterial blood flow 250 and into the flow unit 210wherein the pressure and flow of the arterial blood is regulated by theremote module 270 through use of the chamber 220. Thereafter, thearterial blood having pressure and flow values falling within theappropriate ranges flows into the lumen 18 of the catheter 10 where thearterial blood is perfused in a retrograde fashion into the vein 406 ata target location within the penumbra region 404 of the brain 404.Accordingly, step 520 further comprises the initial inflation anddeflation of the chamber 220 of the flow unit 210 as controlled by theremote module 270, and the initial expansion and deflation of the atleast one expandable balloons 30, 32 of the catheter 10 in accordancewith the systolic and diastolic cycles of the patient's sinus rhythm. Inaddition, due to the pulsatile nature of the sinus rhythm, the vein 406is concurrently allowed to drain the excess blood during the diastoliccycle of the sinus rhythm.

At step 522, the remote module 270 assesses whether or not the datameasured by the at least one sensors 24, 224 of the catheter 10 and theflow unit 210 fall within the acceptable, pre-programmed ranges. Forexample, the remote module 270 may be programmed to take into accountthe arterial blood pressure at the distal end 214 of the flow unit 210during both diastole and systole, the pressure within the vein 406 asthe distal end 14 of the catheter 10 during diastole and systole, theflow rate of the arterial blood through the autoretroperfusion system300 during diastole and systole, or any other types of information thatmay assist with the regulation and delivery of the retroperfusiontherapy.

In the event the remote module 270 detects any deviation in the datafalling outside of the predefined allowable ranges, the method 500proceeds to step 524. At step 524, the remote module 270 makesadjustments to the autoretroperfusion system 300 until the data receivedfrom the sensors 24, 224 indicates that the deviation has been correctedand the data falls within the acceptable parameters. For example, theremote module 270 may adjust the rate of injection and/or withdrawal offluid from the chamber 220 through the at least one port 330.Additionally or alternatively, the remote module 270 may adjust thevolume of fluid injected or withdrawn from the interior 232 of thechamber 220. Accordingly, at step 524, the remote module 270automatically adjusts the flow and/or pressure of the arterial bloodflowing through the flow unit 210 pursuant to the continuous stream ofdata received from the at least one sensor 24 of the catheter 10 and theat least one sensor 224 of the flow unit 210.

When, either at step 522 or step 524, the remote module 270 verifiesthat all of the data parameters are in order, the method 500 advances tostep 526. At step 526, the remote module 270 defines an arterial bloodpressure and flow time cycle based on the data the remote module 270continuously receives from the at least one sensor 24 of the distal end14 of the catheter 10 and the at least one sensor 224 of the distal end214 of the flow unit 210. After the remote module 270 has defined thepressure and flow time cycle, the remote module 270 establishes the samethrough the interval operation of the fluid source 280 and inflationand/or deflation of the chamber 220. In this manner, theautoretroperfusion system 300 delivers continuous autoretroperfusiontherapy to the penumbra 404 of the brain 400 such that the cells withinthe penumbra 404 can be maintained for an extended period of timefollowing an acute stroke event.

The retroperfusion system 300 will continue to cycle driven by theremote module 270 either until a clinician discontinues theautoretroperfusion therapy, or until the data collected by the at leastone sensors 24, 224 and transmitted to the remote module 270 indicatesthat a deviation has occurred in one of the measured parameters thatfalls outside of the acceptable range. In the event the latter occurs,the method 500 will revert to step 524 such that the remote module 270makes adjustments to the injection and/or withdrawal of fluid from thechamber 220 until the data received from the sensors 24, 224 indicatesthat the deviation has been corrected and the data collected all fallswithin the acceptable parameters. Upon correction of the deviation, themethod 500 again will return to step 526.

The autoretroperfusion system 300 and the method 500 enable a clinicianto provide a bridge retroperfusion therapy to a patient suffering from astoke in order to extend the window of viability of the penumbra 406 ofa brain 400 following stroke onset. Accordingly, because the system 300and method 500 extends the timeframe in which the penumbra 406 isviable, the opportunity to effectively use thrombolytic,neuroprotective, and/or other pharmaceutical agents with respect to thetreatment of a stroke is created.

For example and without limitation, in at least one embodiment of themethod 500, a clinician may, at step 526, administer one or morepharmaceutical therapies to the patient in conjunction with theretrograde cerebral perfusion therapy provided at this step 526 by thesystem 300. By continuously providing a controlled arterial blood supplyto the penumbra 404, the method 500 and the autoretroperfusion system300 enables the pharmaceutical agents to establish the appropriatepharmacological concentrations within the area of interest and therebyeffectively attack the underlying cause of the stroke (i.e. the clot).Accordingly, use of the method 500 and the retroperfusion system 300enables not only the provision a successful bridge retroperfusiontherapy capable of minimizing cell death within the penumbra 406, butalso allows for the extension of time during which alternativetreatments, such as prophylactic and/or pharmacological therapies, canbe administered in order to further improve efficacy of treatment andreduce associated complication rates.

It will be appreciated that the method 500 may also be employed todeliver the autoretroperfusion system 200. Accordingly, it will beunderstood that all references to the system 300 in connection with themethod 500 may be interchanged with the system 200; however, in this atleast one embodiment, the method 500 may omit steps 514 and 518altogether as the autoretroperfusion system 200 does not comprise theconnection assembly 310.

Now referring to FIG. 10A, a schematic view of a retroperfusion catheter610 is shown. The catheter 610 is configured similarly to the catheter10, except with respect to the expandable balloons. As the variousembodiments of the catheter 610 will be described in connection with theprovision of retrograde cerebral perfusion therapy to a brain, it willbe understood that the catheter 610 is not limited to use in connectionwith the brain and may be applied to any other areas of the body wherethe characteristics and/or configuration of the catheter 610 may beuseful.

Similar to the catheter 10, the catheter 610 is configured to be placedwithin a venous vessel and comprises a flexible, elongated tube having aproximal end 612, a distal end 614, and a body 616 having a lumen 618.The catheter 610 may be comprised of any suitable material known in themedical arts and the dimensions of the catheter 610 may vary dependingon the particulars of the specific patient or with respect to the veinto be cannulated. For example and without limitation, the catheter 10may be configured for insertion within the cerebral venous system tofacilitate retrograde cerebral perfusion techniques. Furthermore, thecatheter 610 may be coated with heparin or any other suitableanti-coagulant such that the catheter 610 may be placed within a vesselfor an extended period of time without inhibiting the blood flowtherethrough due to coagulation.

As shown in FIG. 10A, the catheter 610 comprises a tapered configurationto facilitate advancement of the distal end 614 of the catheter 610 intothe venous capillaries of the cerebrum or any other narrow vessels asmay be appropriate. While one example of the tapered configuration ofthe catheter 610 is shown in FIG. 10A, it will be appreciated that thecatheter 610 may be configured in any manner, tapered or otherwise, thatallows the distal end 614 of the catheter 610 to be advanced through ablood vessel having a decreasing diameter. The proximal end 612, thedistal end 614, the body 616 and the lumen 618 of the catheter 610 areall configured identically to the related components of the catheter 10.

The body 616 of the catheter 610 extends between the proximal and distalends 612, 614 of the catheter 610 and comprises a plurality of orifices620 disposed along its length. Each of the plurality of orifices 620 areidentical to the plurality of orifices 20 described in connection withcatheter 10 and, similar to the orifices 20, facilitate the controlledintroduction of oxygen-rich arterial blood flowing through the lumen 618of the catheter 610 and into the cerebral venous system. Similar to theorifices 20 of the catheter 10, the size, number and placement of theorifices 620 may be manipulated to affect the pressure and/or flow rateof the arterial blood flowing therethrough and into the venous system.

Similar to the distal end 14 of the catheter 10, the distal end 614 ofthe catheter 610 comprises one or more sensors 624 disposed therein orthereon. While the one or more sensors 624 are described herein as beingpositioned on the distal end 614 of the catheter 610, it will beappreciated that the one or more sensors 624 may be positioned anywhereon or within the body 616 of the catheter 610.

Among other things, inclusion of the at least one sensor 624 on thecatheter 610 can provide information regarding the pressure within thevein into which the catheter 610 is being inserted. In this manner, theat least one sensor 624 can assist a clinician in determining theseverity of ischemic damage to an affected area of the brain, as well aswhether or not the appropriate pressure drop in the retroperfusedarterial blood flow has been achieved upon initiation of theretroperfusion therapy.

The one or more sensors 624 of the distal end 614 may comprise anysensor that may be useful in the medical arts, such as and withoutlimitation, sensors to measure the flow rate within the vein ofinterest, pressure sensors, and/or sensors for measuring the pH, thepartial pressure of carbon dioxide within the vein or oxygen saturation,lactic acid concentration, or temperature of the blood therein. Theinclusion of specific type(s) of sensors 624 on the distal end 614 ofthe catheter 610 may be determined on a case-by-case basis, depending onthe particular needs of the patient at issue. In addition, each of theat least one sensor 624 of the distal end 614 of the catheter 610 may beconfigured as discussed with respect to the at least one sensor 24 ofthe distal end 14 of the catheter 10 and is capable of transmitting thedata collected thereby to an external device (either through wired orwireless transmission). Accordingly, similar to at least one embodimentof the at least one sensor 24 of the catheter 10, each of the at leastone sensors 624 may optionally be coupled with a sensor cable 626 (seeFIG. 11) that is coupled with the remote module 270 (not shown).Furthermore, as described in connection with the catheter 10, thecatheter 610 may similarly be used in conjunction with the sheath 150 toassist in the manipulation of the flow of arterial blood out of theplurality of orifices 620 of the catheter 610 and into the vein.

As shown in FIG. 10A, the catheter 610 may further comprise one or moreexpandable balloons 630, 632 coupled with the external surface of thebody 616 of the catheter 610 such that each of the at least oneexpandable balloons 630, 632 encases the catheter 610. In the at leastone embodiment of the catheter 610 illustrated in FIG. 10A, a firstexpandable balloon 630 is coupled with the body 616 of the catheter 610at a first position and a second expandable balloon 632 is coupled withthe external surface of the body 616 at a second position. Furthermore,the second expandable balloon 632 is positioned distally on the externalsurface of the body 616 relative to the first expandable balloon 630.

Each of the at least one expandable balloons 630, 632 may comprise anyexpandable balloon that is appropriate for insertion within a vessel andmay be formed of any material suitable for this function including,without limitation, polyethylene, latex, polyestherurethane,polyurethane, silastic, silicone rubber or combinations thereof. Inaddition, the at least one balloons 630, 632 may be coated with heparinor any other suitable anti-coagulant such that the at least oneexpandable balloons 630, 632 may be placed within a vessel without therisk of coagulation. The size and configuration of each expandableballoon will differ between patients and applications. In operation,similar to the balloons 30, 32 of the catheter 10, the at least oneexpandable balloon 630, 632 can be used to intermittently occlude thevein and prevent the antegrade flow of blood therethrough and anchor thecatheter 610 in the desired position within a vessel wall.

However, unlike the at least one balloons 30, 32 of the catheter 10, inthis at least one embodiment the balloons 630, 632 of the catheter 610are not capable of automatically expanding and deflating. Accordingly,the interiors of each of the at least one expandable balloons 630, 632are not in fluid communication with the lumen 618 of the catheter 610.Alternatively, in the at least one embodiment shown in FIGS. 10A and10B, the interior of the first expandable balloon 630 is in fluidcommunication with a first balloon port 634, and the interior of thesecond expandable balloon 632 is in fluid communication with a secondballoon port 635. Accordingly, each of the balloons 630, 632 may beexpanded or deflated independently upon the injection or withdrawal offluid therefrom through the respective balloon port 635.

As with the catheter 10, expansion of the at least one expandableballoon 630, 632 of the catheter 610 occludes the venous vessel in whichthe catheter 610 is inserted, prevents the normal antegrade flow ofblood through the venous vessel, and increases the pressure therein. Inthis manner, oxygen-rich arterial blood delivered into the vesselthrough the plurality of orifices 620 and the distal end 614 of thecatheter 610 at a location upstream of the balloon occlusions is forcedto remain within the vein for a period of time and perfuse thesurrounding capillaries. Accordingly, occlusion of the vein by the atleast one expandable balloon 630, 632 of the catheter 610 allows thepenumbral tissue vascularized by the venous vessel at issue to benefitfrom the nutrients contained within the arterial blood.

However, as with the catheter 10, in order to provide an effectiveretroperfusion therapy, it is necessary for the at least on expandableballoons 630, 632 to inflate and deflate in an integral fashion toensure that the venous system is not overloaded and the normal antegradeflow of blood can resume periodically to drain the blood from the vein.Now referring to FIG. 11, at least one embodiment of anautoretroperfusion system 700 is shown. The autoretroperfusion system700 comprises the catheter 610, a flow unit 710, the source of arterialblood flow 250 previously described in connection with theautoretroperfusion systems 200, 300, the remote module 270 previouslydescribed in connection with the autoretroperfusion systems 200, 300,and the fluid source 280 previously described in connection with theautoretroperfusion systems 200, 300. In addition, the retroperfusionsystem 700 may optionally comprise the connection assembly 310 asdescribed in connection with the retroperfusion system 300. As the flowunit 710 is the only component of the retroperfusion system 700 that hasnot been previously described in detail herein, the remainder of thedescription of the system 700 will focus on that component.

Like the flow unit 210 of the autoretroperfusion systems 200, 300, theflow unit 710 is responsible, at least in part, for regulation of thepressure of the arterial blood flow prior to its introduction into thecatheter 610 and ultimately the venous system of the brain. In thismanner, the retroperfusion system 700 can ensure that when the arterialblood flow is first introduced to the vein, the pressure of there-routed arterial blood flow has already been reduced such that thethinner venous vessels are protected and the blood pressure is maintainwithin an acceptable pressure range.

Similar to the flow unit 210 of the autoretroperfusion systems 200, 300,the flow unit 710 of the autoretroperfusion system 700 comprises aproximal end 712, a distal end 714, a body 716 extending between theproximal and distal ends 712, 714, a chamber 720, and an interior 718extending through the chamber 720 and between the proximal and distalends 712, 714 of the flow unit 710. Each of the aforementionedcomponents of the flow unit 710 is comprised identically to the relatedcomponents of the flow unit 210. Accordingly, the distal end 714 of theflow unit 710 further comprises at least one sensor 724 disposedtherein, which may or may not be a wired device having a wire componentthat travels through a sensory port 725 to the remote module 270 (notshown). In addition, the chamber 720 comprises an interior 732 that isin fluid communication with the fluid source 280 (not shown) through atleast one port 730.

The flow unit 710 is capable of controlling the pressure and flow rateof the arterial blood traveling through the interior 718 of the flowunit 710 in the same manner as the flow unit 210. Accordingly, theremote module 270 (not shown) can manipulate the volume of the fluidinjected and withdrawn from the interior 732 of the chamber 720, therebyaltering the diameter of the underlying portion of the interior 718 ofthe flow unit 710. Thus, as with the chamber 220 of the flow unit 210,the chamber 720 of the flow unit 710 is capable of forming a stenosiswithin the interior 718 of the flow unit 710 such that the flow ofarterial blood therethrough is inhibited, and subsequently removing thestenosis (when a sufficient amount of fluid is withdrawn from theinterior 732 of the chamber 720) such that the body 716 and interior 718of the flow unit 710 are maintained at their standard diameters.

In addition to the aforementioned, the flow unit 710 of theretroperfusion system 700 is further capable of inflating and deflatingthe at least one balloons 630, 632 of the catheter 610. Specifically, inat least one embodiment of the flow unit 710, the first and/or secondballoon ports 634, 635 are in fluid communication with the interior 732of the chamber 720 such that any fluid injected or withdrawn therefromnecessarily affects the expansion and/or deflation of the at least oneballoon 630, 632. As such, the flow unit 710 further comprises at leastone conduit in fluid communication with the interior 732 of the chamber720 configured to couple with the at least one balloon port 634, 365 ofthe catheter 610 such that the at least one conduit of the flow unit 710and the at least one balloon port 634, 635 of the catheter 610 aresecurely coupled and in fluid communication.

Where the catheter 610 comprises a first balloon 630 and a secondballoon 632, at least one conduit of the flow unit 710 may be configuredsuch that the balloons 630, 632 can expand in unison and/orindependently. For example and without limitation, where the conduits influid communication with each of the first and second balloons 630, 632are fluidly coupled with the interior 732 of the chamber 720, but do notindependently interact with the remote module 270 (not shown) nor thefluid source 280 (not shown), the first and second balloons 630, 632necessarily expand and deflate in substantial unison (taking intoaccount the varying distances the fluid injected into the interior 732of the chamber 620 must flow through the balloon ports 634, 635 prior toreaching the interiors of the first and second balloons 630, 632).

As shown in FIG. 11, at least one embodiment of the flow unit 710comprises a first conduit 733 and a second conduit 734, both of whichare in fluid communication with the interior 732 of the chamber 720.Furthermore, each of the conduits 733, 734 extends distally from thechamber 720, along the interior walls of the body 716 and into thedistal end 714 of the flow unit 710. In this manner, the first andsecond conduits 733, 734 may be aligned with the first and secondballoon ports 634, 635, respectively such that a secure connection isformed therebetween when the proximal end 612 of the catheter 610 iscoupled with the distal end 714 of the flow unit 710.

In addition to being capable of automatically operating the chamber 720to ensure specific parameters related to the arterial blood flow aremet, the remote module 270 may additionally be programmed to activelyregulate the expansion and deflation of the at least one balloon 630,632 of the catheter 610. For example and without limitation, when thefirst and second balloons 630, 632 are each in independent communicationwith the fluid source 280 (not shown) and/or the remote module 270 (notshown), the remote module 270 can independently control the expansionand deflation of the first and second balloons 630, 632 in order toachieve optimal performance of the catheter 610. It will be understoodthat the remote module 270 operates to expand and deflate the chamber720 of the flow unit 710 (and thus the balloons 630, 632 that, in thisat least one embodiment, are in fluid communication therewith) in anidentical manner as described with respect to the flow unit 210, theremote module 270.

Furthermore, in at least one non-limiting example, based on the datacontinuously received from the sensors 624, 724 of the catheter 610 andthe flow unit 710, the remote module 270 can automatically adjust thevolume of fluid injected into the interior 732 of the chamber 720 (andthus the interiors of the at least one balloon 630, 632 of the catheter610) in order to expand the balloon(s) 630, 632 to a desired size.Accordingly, the expansion of the at least one balloon 630, 632 occludesthe vein in which the catheter 610 is inserted, thereby building thepressure in the venous system, facilitating the perfusion of arterialblood into the capillaries that branch from the vein, and providingsupport to the catheter 610 to prevent against the catheter 610 frombecoming dislodged. Furthermore, the remote module 270 is also capableof automatically adjusting the volume of the fluid withdrawn from theinterior 732 of the chamber 720 (and thus the interiors of the at leastone balloon 630, 632 of the catheter 610) in order to deflate theballoon(s) 630, 632. This, in turn, allows for the normal antegrade flowof blood to drain from the vein and automatically decreases the pressurein the venous system. Accordingly, by driving the periodic expansion anddeflation of the at least one balloon 630, 632 of the catheter 610, theremote module 270 can further manipulate the pressure and flow rateswithin the autoretroperfusion system 700 and prevent the vein frombecoming overloaded.

In at least one embodiment of the autoretroperfusion system 700, theremote module 270 can be driven be an algorithm such that the remotemodule 270 is capable of executing the inflation and deflation of thechamber 720 of the flow unit 710, as well as the expansion and deflationof the at least one balloon 630, 632 of the catheter 610, pursuant to aset of desired flow parameters, pressure and perfusion rates. In otherwords, in this at least one embodiment, the remote module 270automatically manipulates the injection of fluid into and the withdrawalof fluid from the interior 732 of the chamber 720 on an interval basisin order to achieve the arterial blood flow, pressure and any othercriterion of interest within the optimal ranges.

In at least one additional embodiment of the retroperfusion system 700,system 700 may further comprise a fixed stenosis. Specifically, theretroperfusion system 700 may further comprise a stenosis component 810for placement in connection with the source of arterial blood flow 250in such a manner so as to affect the flow of arterial bloodtherethrough. Accordingly, the stenosis component 810 can staticallymanipulate the pressure and/or flow rate of the arterial blood evenprior to its introduction into the proximal end 712 of the flow unit710.

It will be understood that the stenosis component 810 may comprise anyfixed stenosis device known in the art provided the stenosis component810 does not degrade over time, contaminate the system, and/or causecoagulation of the arterial blood. As illustrated in FIG. 11, in atleast one embodiment the stenosis component 810 comprises a devicedesigned to be coupled with the exterior wall of the source for arterialblood flow 250 that is capable of applying external compression theretoin order to facilitate the control of the flow rate and pressure of theblood moving through the source of arterial blood flow 250.Specifically, the stenosis component 810 of FIG. 11 comprises aclamp-like device applied to the exterior wall of the source forarterial blood flow 250 in such a manner so as to reduce the diameter ofthe same.

Despite the at least one example provided in FIG. 11, it will beunderstood that the stenosis component 810 may comprise any means forproviding a fixed stenosis such that a pressure drop is achieved in theblood flowing through the source of arterial blood flow 250. For exampleand without limitation, in at least one additional embodiment, thestenosis component 810 may comprise a coil or internal balloon designedto be positioned within the source of arterial blood flow 250 and topartially occlude the flow of arterial blood therethrough.

In at least one alternative embodiment of the retroperfusion system 700comprising the stenosis component 810, the flow unit 710 is configuredin such a manner that it does not allow for the manipulation of thediameters of the body 716 and/or interior 718 of the flow unit 710.Accordingly, even though fluid may be injected into or withdrawn fromthe interior 732 of the chamber 720 as described previously describedherein, the diameters of the body 716 and interior 718 of the flow unit710 are fixed. Thus, in this at least one embodiment, the remote module270 is solely capable of expanding and deflating the at least oneballoon 630, 632 of the catheter 610 through injection and/or withdrawalof a fluid into the interior 732 of the chamber 720 and all otherregulation of the arterial blood flow rate and/or pressure is achievedusing the stenosis component 810 and/or the fixed diameter of theinterior 718 of the flow unit 710.

Now referring to FIG. 12, a flow chart of a method 900 for providingretroperfusion therapy to a brain is shown. For ease of understanding,the steps of the method 900 described herein will be discussed relativeto the components of the retroperfusion system 700, but it will beappreciated by one skilled in the art that any similar devices and/orsystems can be used to perform this method 900. In addition, while theretroperfusion system 700 and the method 900 are described in connectionwith treating an ischemic area of a brain through catheterization of avenous vessel extending into a penumbral area of a brain, it will beunderstood that the retroperfusion system 700 and the method 900described herein may be applied to perform autoretroperfusion on anyorgan or tissue in need of retroperfusion treatment. Furthermore, itwill be understood that the steps of the method 900 referred to usingthe reference numerals associated with the steps previously described inconnection with the method 500 herein are identical to the steps ofmethod 500 having like reference numerals.

In at least one approach to the method 900, at step 502 a topographicimage of the ischemic area of the brain 400, including the core ischemicinfarct and the ischemic penumbra, is created using conventional imagingtechniques. In this manner, a clinician can determine the location ofthe ischemic infarct and the penumbra. At step 504, an artery ofinterest (not shown) is percutaneously punctured under local anesthesiawith a conventional artery access device or as otherwise known in theart. For example and without limitation, in at least one embodiment, an18 gauge needle is inserted into the desired artery and the source ofarterial blood flow 250 having the stenosis component 810 coupledtherewith is positioned within the artery such that a portion ofarterial blood is re-routed therethrough, driven by the pulsatile rhythmof the beating heart.

At step 506, a vein of interest is percutaneously punctured under localanesthesia with a conventional venous access device or as otherwiseknown in the art. For example and without limitation, in at least oneembodiment, an 18 gauge needle is inserted into the jugular vein. Itwill also be appreciated that any other vein may be utilized, providedthe vein facilitates retroperfusion of the arterial blood to the desiredarea of the body. After the vein has been punctured, at step 508, a softguidewire 40 is inserted into the opening in the vein and advanced intothe penumbra region of the brain. This may be facilitated through use ofthe brain topographic imaging taken at step 502 and/or through x-ray(i.e. fluoroscopy) or other suitable visualization techniques.

After the distal end of the guidewire 40 is positioned in the desiredlocation within the penumbra of the brain, the distal end 614 of thecatheter 610 is inserted into the vein following the guidewire 40 atstep 510. Specifically, the distal end 614 of the catheter 610 isthreaded over the guidewire 40, inserted into the vein and advancedalong the main venous system to the target area within the penumbra.Step 510 may be performed under fluoroscopic control or with the aide ofother visualization techniques known in the art. Thereafter, theguidewire 40 may optionally be withdrawn from the body through the lumen18 of the catheter 10 at step 512.

At step 514, the connection assembly 310 may optionally be coupled withthe proximal end 612 of the catheter 10 and the distal end 714 of theflow unit 710. The connection assembly 310 is fitted over the distal end714 of the flow unit 710 and the proximal end 612 of the catheter 610and forms a leak-free attachment with both components 610, 710.Furthermore, in the at least one embodiment of the method 900 where theat least one guidewire 40 was not withdrawn from the patient's body atstep 512, the proximal end of the at least one guidewire 40 is threadedthrough the distal end 314 and the limb component 318 of the connectionassembly 310 such that the at least one guidewire 40 extends through theinterior 322 of the limb component 318.

At step 516, the flow unit 710 is coupled with the source of arterialblood flow 250 and begins to receive arterial blood from the puncturedartery within the interior 718 thereof. In this manner, the arterialblood re-routed from the artery of interest (not shown) by the source ofarterial blood flow 250 is allowed to flow through the source ofarterial blood flow 250 and into the proximal end 712 of the flow unit710 in a pulsatile fashion pursuant to the rhythm of the patient'sheartbeat. In addition, due to the inclusion of the stenosis component810 on or in the source of the arterial blood flow, the flow rate and/orpressure (depending on the configuration of the particular stenosiscomponent 810) is adjusted as the arterial blood flows past the locationof the source of arterial blood flow 250 where the stenosis component810 is coupled therewith.

At step 514, the proximal end 612 of the catheter 610 and the distal end714 of the flow unit 710 are securely coupled together. In the at leastone embodiment of the retroperfusion system 700 that further comprisesthe connection assembly 310, at step 518 the connection assembly 310initiates the injection of gas into the interiors 320, 322 of the body316 and the limb component 318 such that the proximal end 612 of thecatheter 610 and the distal end 714 of the flow unit 710 may be securedtogether under sterile conditions. In addition, at step 518, if the atleast one guidewire 40 has not previously been withdrawn from thepatient's body through the lumen 618 of the catheter 610 at step 512,the at least one guidewire 40 is now removed from the patient throughthe limb component 318 of the connection assembly 310.

At step 920, the distal end 214 of the flow unit 210 and the proximalend 12 of the catheter 10 are securely coupled with one another and thearterial blood from the artery of interest is pumped in synchrony withthe patient's sinus rhythm through the source of arterial blood flow250, past the stenosis component 810, and into the flow unit 710. In theat least one embodiment of the retroperfusion system 700 where thediameter of the interior 718 of the flow unit 710 is dynamicallyregulated by the remote module 270, the pressure and flow of thearterial blood is further regulated by the remote module 270 through useof the chamber 720. Thereafter, the arterial blood having pressure andflow values falling within the appropriate ranges flows into the lumen618 of the catheter 610 where the arterial blood is perfused in aretrograde fashion into the vein at a target location within thepenumbra region of the brain. Accordingly, in at least one embodiment,step 920 further comprises the initial manipulation of the diameter ofthe interior 718 of the flow unit 710 and the initial expansion anddeflation of the at least one expandable balloon 630, 632 of thecatheter 610 as controlled by the remote module 270. However, it will beunderstood that, in the at least one embodiment of the retroperfusionsystem 700 wherein the interior 718 of the flow unit 710 is fixed, step920 does not include manipulation of the interior 718 diameter and, assuch, the remote module 270 only facilitates the initial expansion anddeflation of the at least one expandable balloon 630, 632 of thecatheter 610.

At step 522, the remote module 270 assesses whether or not the datameasured by the at least one sensors 624, 724 of the catheter 610 andthe flow unit 710 fall within the acceptable, pre-programmed ranges. Inthe event the remote module 270 detects any deviation in the datafalling outside of the predefined allowable ranges, the method 900proceeds to step 924. At step 924, the remote module 270 makesadjustments to the autoretroperfusion system 700 until the data receivedfrom the sensors 624, 724 indicates that the deviation has beencorrected and the data falls within the acceptable parameters. Forexample, in the at least one embodiment of the retroperfusion system 700wherein the interior 718 of the flow unit 710 is fixed, the remotemodule 270 may adjust the rate at which the at least one balloon 630,632 of the catheter 610 is expanded and deflated in order to manipulatethe flow and/or pressure values of the arterial blood perfusing throughthe catheter 610 and into the vein. Alternatively, where the diameter ofthe interior 718 of the flow unit 710 is adjustable, the remote module270 may adjust the rate of injection and/or withdrawal of fluid from thechamber 220 and/or the volume of fluid injected or withdrawn from theinterior 232 of the chamber 220 in order to affect the expansion anddeflation of the balloons 630, 632 and/or the diameter of the interior718 (and thus degree of stenosis) of the flow unit 710. Accordingly, atstep 924, the remote module 270 automatically adjusts the flow and/orpressure of the arterial blood flowing through the flow unit 710pursuant to the continuous stream of data received from the at least onesensor 624 of the catheter 610 and the at least one sensor 724 of theflow unit 710.

When, either at step 522 or step 924, the remote module 270 verifiesthat all of the data parameters are in order, the method 900 advances tostep 526. At step 526, the remote module 270 defines an arterial bloodpressure and flow time cycle based on the data the remote module 270continuously receives from the at least one sensor 624 of the distal end614 of the catheter 610 and the at least one sensor 724 of the distalend 714 of the flow unit 710. After the remote module 270 has definedthe pressure and flow time cycle, the remote module 270 establishes thesame through the interval operation of the fluid source 280 andinflation and/or deflation of the balloons 630, 632 and/or, ifapplicable, the adjustment of the diameter of the interior 718 of theflow unit 710. In this manner, the autoretroperfusion system 700delivers continuous autoretroperfusion therapy to the penumbra of thebrain such that the cells within the penumbra can be maintained for anextended period of time following an acute stroke event.

The devices, systems and methods described herein provide numerousbenefits over the devices, systems and methods of the prior art. Thesystems 200, 300, 700 allow for a bridge retroperfusion therapy to besafely delivered to stroke patients such that other treatment therapiesthat were previously not available may be applied. Furthermore, thedevices, systems and methods described herein are minimally invasive,completely reversible, and decrease the risk of complications seen withconventional treatments.

While the devices, systems and methods described herein are presentedwith respect to specific anatomy and treatment examples, as one ofordinary skill in the art would recognize, the systems 200, 300 and 700,the components thereof, and the methods 500, 900 may be expanded to anyorgan, limb or body structure that would benefit from a safe andcontrollable retroperfusion therapy.

In addition to the foregoing, and in various embodiments of catheters10, 610 and/or systems 200, 300, and 700, for example, of the presentdisclosure, catheters 10, 610 and/or systems 200, 300, and 700 mayoptionally comprise a regional hypothermia system 4000 configured inaccordance with the following. Various regional hypothermia systems 4000of the present disclosure, as shown in component block diagram of FIG.13 and as referenced in further detail herein, are configured for use tocool (reduce the temperature of) blood and/or other fluids within thebody for targeted delivery to a location within the body. Such coolingcan be from, for example, at or about 0.5° C. to as much as 10° C.cooler, for example, than the native temperature of blood within themammalian body. In some embodiments, localized blood cooling of greaterthan 10° C. may be desired and accomplished using one or more regionalhypothermia systems 4000 of the present disclosure.

In various embodiments, regional hypothermia systems 4000 are configuredfor use within a mammalian body even at tissues that are relativelydifficult to reach due to, for example, potential occlusion of one ormore coronary and/or cerebral arteries. Such regional hypothermiasystems 4000 of the present disclosure may be useful in connection withthe reduction of perfusion injuries by cooling the region of risk,whether it be at, near, or in the heart and/or brain, may be critical toreduce reperfusion injury and to decrease infarct size, for example,prior to opening an artery in the heart or brain. Retroperfusion, asreferenced generally herein, provides an ideal mechanism to deliverblood at a target location, and the use of a regional hypothermia system4000 of the present disclosure in connection with one or more catheters10, 610 and/or systems 200, 300, and 700 of the present disclosure caneffectively deliver blood at a desired/targeted temperature by way ofdelivery through open veins, for example, to the region at risk, such asa heart or brain. In general, catheters 10, 610 and/or systems 200, 300,and 700, in connection with the use of one or more regional hypothermiasystems 4000 of the present disclosure, can allowperfusion/retroperfusion of oxygenated blood, control blood perfusionpressure within a vessel, condition a blood vessel to operate underhigher blood pressure (such as arterialization of a vein), and/orincrease flow of oxygenated blood to ischemic tissue, all at arelatively colder temperature than would otherwise be allowed withoutthe use of a regional hypothermia system.

In at least one embodiment of a regional hypothermia system 4000 of thepresent disclosure, and as shown in FIG. 13, regional hypothermia system4000 comprises a heat exchanger 4002 coupled to one or more componentsof catheters 10, 610 and/or systems 200, 300, and 700 of the presentdisclosure, such as, for example, catheters 10, 610, flow unit 210, 710,body 216, 316, 716, and/or other components referenced herein. Heatexchanger 4002, in various embodiments, is configured to reduce thetemperature of blood passing through one or more components of catheters10, 610 and/or systems 200, 300, and 700, so that the blood that isultimately delivered to the targeted area of interest, such as being at,near, or in the heart and/or brain, is at a lower temperature thannormal (or without the use of a regional hypothermia system 4000). Forexample, and in at least one embodiment, regional hypothermia system4000 is used to reduce the temperature of blood delivered at, near, orin the heart and/or brain by or about 3° C. to 4° C. via the generalblood circuit created using various catheters 10, 610 and/or systems200, 300, and 700.

Heat exchanger 4002, as referenced herein, can utilize one or morecooling products 4004, such as perfluorocarbon, liquid carbon dioxide,helium, another cooled gas, and/or another refrigerant or refrigerationmechanism known in the art, that facilitates the cooling of blood, andultimately tissues at or near the cooled blood, through components ofcatheters 10, 610 and/or systems 200, 300, and 700 of the presentdisclosure. Furthermore, one or more temperature sensors 4006 can becoupled to various components of catheters 10, 610 and/or systems 200,300, and 700 of the present disclosure, catheters 10, 610, flow unit210, 710, body 216, 316, 716, and/or other components referenced herein,so that blood and/or tissue temperature(s) (including temperatures at,near, or in the heart and/or brain, depending on the type of catheters10, 610 and/or systems 200, 300, and 700 used) can be detected bytemperature sensors 4006 and transmitted (via wire or wirelessly) to aremote module 270 and/or another data acquisition and processingsystem/mechanism so that a user of regional hypothermia system 4000 canregulate localized temperature (at, near, or in the heart or brain, forexample), as desired. A generic device 4008 is shown in FIG. 13 as beingoperably coupled to an exemplary regional hypothermia system 4000 of thepresent disclosure, whereby generic device 4008 may comprise one or morecatheters 10, 610 and/or systems 200, 300, and 700, other devices and/orsystems of the present disclosure, and/or individual components thereof.An exemplary kit 4010 of the present disclosure, as shown in thefigures, comprises an exemplary regional hypothermia system 4000operably coupled to an exemplary generic device 4008 of the presentdisclosure.

Further, and in various embodiments, heat exchanger 4004 can be at thelevel of an arterial-venous connector, a double-lumen catheter, and/oranother component of one or more cannulas 100, 200, and 400 and/orgrafts 302 of the present disclosure. Use of the same can beparticularly important for patients are at high risk for reperfusioninjury and/or patients with hemodynamics instability. There are severaladvantages to using a regional hypothermia system 400 of the presentdisclosure, including but not limited to rapid percutaneous insertionand rapid cooling of the desired area (such as at or near the brain)before opening the culprit artery to avoid the cascade of inflammatoryreactions responsible for reperfusion injury.

As referenced generally above, various regional hypothermia systems 4000of the present disclosure are configured and operable to introduce mildhypothermia to reduce cerebral infarct size and general severity of thesame. Such systems 4000, in connection with various catheters 10, 610and/or systems 200, 300, and 700 of the present disclosure, can treatchronic and acute heart failure, as needed.

Heart disease continues to be the leading cause of death in the US andworldwide, with coronary artery disease (CAD) being the most common typeof heart disease causing acute coronary syndromes (ACS). ST segmentelevation myocardial infarction (STEMI) is the most severe form of ACSaffecting nearly half a million Americans each year. Contemporarytreatment of STEMI includes prompt and successful reperfusion witheither percutaneous coronary intervention (PCI) or thrombolytic therapyto limit myocardial injury and improve clinical outcome. Restoration ofblood flow through an obstructed artery, however, may lead toreperfusion injury (RI) or microvascular obstruction in at least 60% ofall STEMI patients. RI, as well as no-reflow phenomenon, lead tomultiple complications including arrhythmias, cellular and interstitialedema, increased infarct size, left ventricular (LV) dysfunction, LVremodeling, and increased mortality. Numerous modalities of treatmentwith pharmacologic agents and ischemic pre- and post-conditioning havebeen investigated for the treatment of RI, but currently there is nowidely accepted clinical method to reduce RI. Therefore, novelapproaches are needed to limit RI without first opening the arterialobstruction (i.e., pre-conditioning).

Mild hypothermia (MH), defined as a temperature of 32° C.−35.9° C.,provides cardio-protection and decreases infarct size following a STEMIby reducing myocardial metabolic demand, free radical production, andplatelet aggregation. Clinical translation of these cardio-protectiveresults, however, has not been successful because of an inability tolocally cool the ischemic region prior to PCI. Since traditionalendovascular methods can only locally cool the ischemic myocardium afterPCI (when hypothermia is unlikely to be effective), full clinicalutility requires a new percutaneous route for local MH delivery to theischemic region prior to PCI. Unlike the obstructed coronary arterialsystem, the coronary venous system remains unobstructed and thus hasgreat potential for therapy delivery (retrograde delivery of arterialblood flow with and without MH). To date, therapeutic retroperfusion hasnot been adopted clinically because complicated equipment is required toregulate perfusion to prevent damage to the entire coronary venoussystem when exposed to arterial pressures.

The purpose of the present study was to evaluate the effects ofselective autoretroperfusion (SARP) and MH-SARP on RI when appliedfollowing coronary artery occlusion but before reperfusion. A novel SARPcatheter that has been validated regulates the pressure reaching thevenous system to locally deliver cooled arterial blood to the ischemicregion of the myocardium.

Materials and Methods

All animal experiments were performed in accordance with national andlocal ethical guidelines, including the Guide for the Care and Use ofLaboratory Animals, the Public Health Service Policy on Humane Care andUse of Laboratory Animals, and the Animal Welfare Act, and an approvedCalifornia Medical Innovations Institute IACUC protocol regarding theuse of animals in research.

Animal Preparation

Twenty female Yorkshire domestic swine were divided in three groups,normothermia SARP (n=7), mild hypothermia SARP (n=6), and sham control(n=7), with body weight of 49.2±5.4 kg. The animals were housed atCalifornia Medical Innovations Institute—Animal Care Facilities. Thepigs had ad libitum access to water and were fed a commercial diet(Teklad 8753). A room temperature of 68-72° F. and humidity of 30% to70% were maintained. The animals were carefully checked for preexistingdiseases and acclimated for a minimum of 3 days before undergoing theinterventional procedures. The pigs were fasted overnight. Sedation wasachieved with ketamine, 20 mg/kg IM, and surgical anesthesia wasmaintained with isoflurane 1.5-2.5%. Ventilation with 100% O₂ wasprovided with a ventilator and maintained PCO₂ at approximately 35 mmHg.Body temperature was kept at 36.0° C.-37.2° C. with a heating pad and aBair Hugger system. Electrocardiographic (ECG) leads were attached tothe animals' limbs and cardiac electrical signals were monitored on aPhysio-Control Lifepak 12 monitor/defibrillator and a PowerLab dataacquisition system (ADInstruments, Colorado Springs, Colo.) for offlineECG analysis. The analysis was performed using LabChart (ADInstruments,Colorado Springs, Colo.) ECG analysis pre-settings for swine: QRS width40 ms, R-R waves 200 ms, Pre-P baseline 50 ms, Maximum PR 140 ms,Maximum RT 400 ms, and ST height 60 ms from alignment.

Under sterile conditions, introducer sheaths were percutaneouslyinserted into the jugular veins and common femoral arteries. Heparin,100 IU/kg IV, was administered before instrumentation and was thensupplemented with 5,000 IU every hour. The left anterior descending(LAD) artery was accessed using a percutaneous femoral approach. A 3-mmMaverick over-the-wire balloon catheter (Boston Scientific, Marlborough,Mass.) was inserted through the right femoral artery and positionedunder fluoroscopic guidance into the LAD artery, distal to the seconddiagonal branch.

The temperature of the subendocardium was measured via a sterile custompercutaneous temperature probe comprised of a 5F radial catheter with an18 gauge needle affixed within the distal tip of the catheter such that3.5 mm of the needle protruded from the catheter. Before sterilization,a thermocouple was passed through the catheter and the tip of thethermocouple was secured in the bevel of the needle with epoxy. Thecatheter was sealed on the proximal and distal ends to ensure hemostasisthroughout the procedure. The temperature probe was advanced through theleft femoral artery into the LV until the catheter was apposed againstthe myocardial wall within the LAD area at risk, thus ensuring a 3.5 mmmeasurement depth. The temperature measurement was determined via a dataacquisition system and recorded via LabChart (ADInstruments, ColoradoSprings, Colo.). The baseline temperature was recorded prior toinitiation of therapy. A representative experimental tracing recordedfrom the subendocardial temperature probe is shown in FIG. 14.

The SARP catheter was inserted through the right jugular vein, advancedinto the coronary sinus, and positioned at the junction of the greatcardiac and LAD veins. With all catheters in place, baselinemeasurements (echocardiography, blood sample collection, arterialpressure and ECG recording) were taken before initiation of theprocedure.

Mild Hypothermia-Selective Autoretroperfusion (MH-SARP) System

The system was comprised of an arterial access sheath, an extracorporealPeltier cooling system used in conjunction with a stainless steel heattransfer heat exchanger, an inline drug delivery port, a flow controlmechanism, and the custom delivery SARP catheter. The catheter wassimilar to an Ansel I sheath with a custom proximal fitting tofacilitate blood flow, and a compliant balloon on the distal section ofthe catheter to ensure occlusion of the great cardiac vein in order toavoid back flow towards the coronary sinus during SARP therapy. Thesecomponents were interconnected via luer-to-barb fittings and siliconetubing. Arterial blood, shunted from the right carotid artery, passedvia silicone tubing through the heat exchanger, and was then deliveredto the LAD vein (including the drug delivery port and flow controlmechanism) connected to the SARP catheter. The arterial blood wasdelivered into the LAD vein using the animal's own pulse pressure (i.e.,autoretroperfusion) without the need of synchronized pumps.

In all three groups, the LAD artery was occluded for 60 min and thenreperfused for 30 min. The control group received no treatment. In thenormothermia SARP and mild hypothermia SARP groups, therapy wasinitiated following 30 min of LAD artery occlusion, and instituted for30 min while the artery remained occluded. To assess the effect oftherapy on longer ischemic periods, in one SARP animal we occluded theLAD artery for 90 min and instituted SARP at 60 min post-occlusion. Inone sham control animal, on the other hand, we reduced the occlusionperiod to 30 min, followed by reperfusion. These two additional animalswere not considered in the analysis.

The heart was defibrillated if fibrillation occurred during theocclusion period. Ventricular arrhythmias during occlusion were managedwith Lidocaine, 1-1.5 mg/kg IV and Amiodarone, 0.5 mg/min IV. After theprocedure, the animals received antibiotics and painkillers, and werefollowed-up for 4 weeks.

Echocardiography

Two-dimensional transesophageal and transthoracic echocardiograms wereobtained in all animals using an iE33 ultrasound system (Philips,Andover, Mass.) for serial measurements of LV function. Long and shortaxes views were obtained during the surgical procedure at 30-minintervals and analyzed offline to determine LV volumes, ejectionfraction (EF), and wall thickness using QLAB 10.5 (Philips, Andover,Mass.). Additional echocardiograms were obtained every two weeks.

Blood Sample Collection

Arterial blood, coronary venous blood, central venous blood, andretroperfusion effluent blood samples were collected every 30 min todetermine metabolic parameters including oxygen tension, glucose uptake,lactate uptake, and cardiac troponin I (cTnI) levels. miR-1 and miR-133alevels were measured in plasma. The retroperfusion effluent samples wereobtained via the lumen of the LAD balloon catheter while inflated.

Reverse Transcription and Quantitative Real Time PCR Analysis

MicroRNA (miRNA or miR) assays were performed as described previously(21). Plasma was mixed with TRIzol LS (Invitrogen, Carlsbad, Calif.,USA) in a 1:3 ratio and the samples were homogenized by vortexing >30 s.RNA was then isolated using an miRNeasy mini kit (Qiagen, Hilden,Germany) according to the manufacturer's instructions. Reversetranscription and quantitative PCR (qPCR) were performed using theTaqMan@ microRNA assay Kit (Applied Biosystems) as previously described.Briefly, reverse transcription was performed in a 15 μL reaction mixcontaining 20 ng of total RNA, 3 μL of miRNA primer mix, 1 mM dNTP, 50 Ureverse transcriptase, and 3.8 u RNase inhibitor. Reactions wereincubated at 16° C. for 30 min, 42° C. for 30 min, and 85° C. for 5 min.PCR was performed in a 10 μL reaction volume containing 0.5 μL of miRNAprimer and TaqMan probe mix, 0.67 μL of RT product (five-fold dilution),and 5 μL of TaqMan Universal PCR Master Mix. The cycling conditions wereas follows: 10 min at 95° C., followed by 40 cycles of 15 s at 95° C.and 1 min at 60° C. miR-16 was used as an internal control. For allsamples, reverse transcription and qPCR were performed three times andqPCR was performed in triplicate. Relative gene expression levelsbetween baseline and 90 min samples were determined using thecomparative Ct (2^(−ΔΔCt)) method after normalizing to miR-16. Thebaseline values were normalized to 1.

Heart Preparation

After four weeks of the initial interventional procedure, the heart wasarrested in diastole with a saturated solution of potassium chlorideinjected through the jugular vein, excised and transported to the lab in0.9% sodium chloride. Transmural biopsy samples were taken fromdifferent regions of the LV for histological analysis. The LAD arterywas cannulated with tygon tubing at the site where the balloon catheterwas inflated during the SARP procedure. The myocardium wasdouble-stained with Evans blue and 2,3,5-triphenyltetrazolium chloride(TTC) for demarcation of the area at risk and the infarcted area. Theheart was perfused with 10 mL of 1% Evans blue. The ascending aorta andpulmonary artery were removed, as well as the atria and the rightventricle. The LV was then cut into 8 slices (˜10 mm thick) from apex tobase (parallel to the atrioventricular groove). The slices were furtherstained with 1% TTC at 37° C., fixed in 10% buffered formalin, andscanned for determination of infarct size relative to the area at riskusing ImageJ software.

Statistical Analysis

All statistical analyses were performed using SigmaStat 3.5 (SystatSoftware, Point Richmond, Calif.). The data were expressed as mean±SD,unless otherwise specified. The differences between the variousparameters and groups were evaluated using analysis of variance (ANOVA)and Student's t-test. The differences were considered significant atp<0.05.

Results

The hemodynamic parameters in the control, normothermia and hypothermiagroups at baseline, occlusion, retroperfusion, and reperfusion periodsare summarized in Table 1.

TABLE 1 Hemodynamic Parameters Control Normothermia Hypothermia BaselineSystolic BP (mmHg) 81.1 ± 7.5  84.2 ± 8.4  81.4 ± 7.0  Diastolic BP(mmHg) 53.6 ± 8.0  58.1 ± 11.4 53.9 ± 8.1  MAP (mmHg) 66.1 ± 8.4  70.6 ±10.6 65.3 ± 7.3  Heart Rate (bpm) 85.4 ± 11.9 85.7 ± 26.8  95.3 ± 31.8Pulse Pressure (mmHg) 27.5 ± 2.8  26.1 ± 5.1  27.5 ± 6.2  IschemiaSystolic BP (mmHg) 61.5 ± 5.9³  65.8 ± 11.7² 59.3 ± 4.1³ Diastolic BP(mmHg) 46.8 ± 6.0³ 48.0 ± 10.3 42.4 ± 5.2  MAP (mmHg) 54.1 ± 6.4²  55.7± 12.1¹ 49.7 ± 5.1² Heart Rate (bpm) 85.2 ± 10.1 88.6 ± 26.1  95.9 ±17.0 Pulse Pressure (mmHg) 14.7 ± 2.0³ 17.9 ± 2.7²  17.0 ± 2.5²Retroperfusion Systolic BP (mmHg) 65.5 ± 7.1²  59.1 ± 5.0³ Diastolic BP(mmHg) 48.6 ± 7.2  43.5 ± 5.1  MAP (mmHg) 56.3 ± 7.7²  50.4 ± 5.4³ HeartRate (bpm) 86.9 ± 14.9  98.8 ± 14.8 Pulse Pressure (mmHg) 16.8 ± 1.7 15.6 ± 2.2  Reperfusion Systolic BP (mmHg) 51.7 ± 7.8³  67.5 ± 6.9^(2,5) 70.5 ± 5.8^(1,6) Diastolic BP (mmHg) 34.4 ± 9.5² 46.3 ± 8.3⁴  44.8 ±6.2⁴ MAP (mmHg) 42.3 ± 8.9³  54.8 ± 8.1^(3,4)  54.4 ± 6.3^(1,4) HeartRate (bpm) 78.0 ± 17.1 105.6 ± 36.7   97.5 ± 14.7⁴ Pulse Pressure (mmHg)17.3 ± 2.8³ 21.2 ± 5.2  25.7 ± 4.4⁵ ¹p < 0.05, ²p < 0.01, ³p < 0.001relative to baseline values. ⁴p < 0.05, ⁵p < 0.01, ⁶p < 0.001 relativeto control group. BP, blood pressure. MAP, mean arterial pressure.

In all 3 groups, the systolic and mean arterial pressure (MAP)significantly decreased during occlusion, retroperfusion and reperfusioncompared with their corresponding baseline values. Systolic pressure andMAP during reperfusion, however, were significantly higher in thenormothermia and hypothermia groups than the control group. Similarly,in the control group, pulse pressure significantly decreased duringocclusion and reperfusion. In the normothermia and hypothermia groups,pulse pressure also significantly decreased during occlusion, remainedapproximately the same during retroperfusion, but returned to almostbaseline levels during reperfusion. Compared with controls, thehypothermia group showed a significantly higher pulse pressure duringreperfusion. Heart rate remained comparable in all 3 groups underdifferent conditions relative to baseline values. During the reperfusionperiod, however, the hypothermia group showed significant increase inheart rate compared with the control group.

Following the initiation of MH-SARP in the corresponding animal group,the myocardial temperature in the subendocardium decreased approximatelyone degree Celsius (35.9° C.±0.3° C. to 35.0° C.±0.2° C.) in less than 4min, as shown in FIG. 14. Once MH-SARP treatment was terminated at 60min post LAD occlusion, the subendocardial temperature progressivelyincreased to baseline levels in approximately 15 min (FIG. 14).

No significant differences in LV function were observed between groupsat the end of the study. EF was modestly reduced from 61.2%±2.7%,59.0%±8.2%, and 58.6%±4.5% at baseline to 58.0%±10.1%, 53.7%±4.0%, and58.9%±7.8% at 4 weeks for control, normothermia, and hypothermia groups,respectively.

The analysis of ECG ST-segment deviation demonstrated significantrecovery in the degree of segment depression within 10 min followinginitiation of therapy (SARP and MH-SARP vs. control, p<0.05, FIG. 15A).Significant reduction in the number of arrhythmic events (FIG. 15B) andabsence of QRS distortion during the reperfusion period were alsoobserved with SARP and MH-SARP (p<0.05).

Cardiac troponin levels in the control, normothermia, and hypothermiagroups are shown in FIG. 16. Significant reduction in cTnI levels wasobserved at 90 min and 2.5 hours following LAD occlusion with SARP(4.4±3.5 ng/mL, p<0.05 and 16.8±16.0 ng/mL, p<0.01) and MH-SARP (1.4±0.8ng/mL, p<0.01 and 8.1±6.8 ng/mL, p<0.001) vs. control (14.2±9.0 ng/mLand 42.6±13.5 ng/mL).

The levels of miR-1 (FIG. 17A) and miR-133a (FIG. 17B), novel biomarkersof reperfusion injury, were measured in blood plasma. A seven-foldincrease in miR-1 after reperfusion was observed in the control groupcompared to baseline (p<0.04). In the normothermia and hypothermiagroups, the values decrease to three and four times of those of baselinevalues, respectively, but the difference were not significant.Similarly, miR-133a in the control group also increased seven timesafter reperfusion, compared to the baseline levels (p<0.02). In thenormothermia group, miR-133a also increased approximately seven times at90 min, although the values were not statistically different tobaseline. In the hypothermia group, the values between baseline and 90min were nearly identical.

A reduction in infarct size (relative to the area at risk) was observedwith SARP (83.2%) and MH-SARP (93.3%) relative to control (FIG. 18A).The infarcted area decreased from 28.1%±7.7% [median 27.1% (quartiles1-3, 25.5-29.6%)] in the control group to 4.7%±4.0% [median 3.9%(quartiles 1-3, 1.7-9.0%)] in the normothermia group (p=0.0001) and1.9%±1.4% [median 1.8% (quartiles 1-3, 0.8-3.2%)] in the hypothermiagroup (p=0.0001). No significant differences were found between SARP andMH-SARP (p=0.15). The 1 pilot animal with 90 min LAD occlusion and 30min SARP treatment showed similar infarcted area (0.7%) to thenormothermia group animals (0% to 9.9%). On the other hand, the 1 pilotcontrol animal with 30 min occlusion followed by reperfusion also showedsimilar infarcted area (22.5%) to the rest of the animals in the controlgroup (16.8% to 42.8%). FIG. 18B shows myocardial sections obtained fromapproximately the same regions in the control, normothermia, andhypothermia groups, double-stained with Evans blue and TTC. Theinfarcted area (white) is clearly demarcated in the control group (leftpanel) vs. normothermia (central panel) and hypothermia (right panel)groups.

FIGS. 19A, 19B, 19C, and 19D show representative histological myocardialsections stained for the RI marker caspase-3. Caspase-3 expression (red)was elevated in control (FIG. 19B) specimens, compared with SARP (FIG.19C) and MH-SARP (FIG. 19D) samples, which approximate healthy viablemyocardium (FIG. 19A).

Indices of cardiac metabolism in response to SARP and MH-SARP are shownin FIGS. 20A, 20B, and 20C. PO₂ levels measured from effluent samples(FIG. 20A) in the control group remained almost the same at 30 and 60min of occlusion (18.1±3.9 mmHg and 19.8±2.7 mmHg, respectively)compared with baseline levels (18.0±4.6 mmHg). In the normothermiagroup, PO₂ levels increased from 17.8±1.5 mmHg at baseline to 35.2±5.5mmHg (p<0.01) and 28.6±9.0 mmHg after 5 and 30 min of SARP,respectively. Similarly, PO₂ levels in the hypothermia group increasedfrom 20.8±3.7 mmHg at baseline to 28.3±4.1 mmHg after 5 min of MH-SARPand 27.0±1.6 mmHg after 30 min of MH-SARP. The values betweennormothermia and control groups were significantly different after 5(p<0.01) and 30 (p<0.01) min of therapy, respectively. In thehypothermia group significance was found after 30 min of therapy(p<0.01) when compared with control. FIG. 20B shows glucose uptakemeasured from effluent samples. Within 5 min of SARP, glucose uptakeincreased to 24.0±2.1 mg/dL (p<0.01), and after 30 min to 18.0±3.3 mg/dLcompared with baseline values (8.4±4.7 mg/dL) in the normothermia group.In the hypothermia group, the values were 28.0±3.4 mg/dL (p<0.01) and20.2±4.0 mg/dL after 5 and 30 min of MH-SARP, respectively, comparedwith 9.7±9.2 mg/dL at baseline. Glucose uptake in the normothermia(p<0.01) and hypothermia (p<0.01) groups was significantly higher thanthe control group after 5 minutes of treatment. FIG. 20C shows lactateuptake measurements from effluent samples. After 5 min of SARP, lactateuptake significantly decreased from 0.4±0.2 mmol/L (baseline) to−4.4±2.0 mmol/L in the normothermia group (p<0.01). After 30 min ofSARP, lactate uptake was −1.5±0.6 mmol/L (p<0.001). Similarly, in thehypothermia group, lactate uptake significantly decreased from 0.6±0.4mmol/L at baseline to −2.6±1.3 mmol/L after 5 min of MH-SARP, and to−1.4±0.8 mmol/L after 30 min of MH-SARP. The values in the normothermiaand hypothermia groups were significantly different after 5 (p<0.01,p<0.01) and 30 (p<0.001, p<0.05) min of treatment, respectively,compared with the control group.

Discussion

We have shown for the first time that selective autoretroperfusion,alone or in combination with mild hypothermia, significantly reducesmyocardial infarct size up to 98% in a swine model of acute myocardialinfarction. MH-SARP was remarkably effective in reducing myocardialinfarct size [98.1±1.4% (93.3% relative to control)], with concomitantattenuation of markers for myocardial ischemia (cTnI), reperfusioninjury (degree of ST-segment depression), and cardiomyocyte injury(oxygen, glucose and lactate uptake, as well as caspase-3 expression).Moreover, SARP alone was also able to significantly reduce infarct size[95.3±4.0% (83.2% relative to control)] and all associated indices tonear equivalent levels without the complexity of hypothermia.

Several animal and clinical studies have documented the beneficialeffects of hypothermia to minimize myocardial reperfusion injuryfollowing AMI. Similarly, the beneficial effects of coronary venousretroperfusion for the ischemic myocardium, with and withoutsynchronized pumping have been largely investigated. In the presentstudy, we sought to evaluate the adjunctive therapeutic effects of bothautoretroperfusion (without the use of synchronized pumps) and mildhypothermia to prevent the deleterious effects of myocardial reperfusionfollowing PCI post-acute coronary occlusion. We used the animals' ownpulse pressure to retroperfuse arterial blood through the coronaryvenous system. We also chose a large animal model (swine) of myocardialischemia to minimize the variability in infarct size and maintaintranslational relevance.

Employing the animals' own pulse pressure, arterial blood from thecarotid was rapidly cooled down using an extracorporeal cooling systemand then retroperfused through the coronary venous system without theneed for external pumps. Furthermore, with the use of regionalhypothermia instead of whole body hypothermia, we avoided hemodynamicdeterioration and other adverse effects such as shivering.Subendocardial temperature was reduced by approximately one degreeCelsius in <4 min following initiation of therapy. This small reductionin temperature provided an additive protective effect to SARP (95.3±4%to 98.1±1.4% infarct size reduction), salvaging the ischemic myocardiumfrom irreversible damage. The remarkable reduction in infarct sizeobserved in the present study is likely the combined effects of bloodsupply reaching the ischemic area, removal of adverse metabolites(retroperfusion), and reduction in cellular metabolism (hypothermia),i.e., positively affecting the oxygen supply-demand relation. The rapiddecrease in subendocardial temperature also supports the effectivedelivery of SARP, which in this case, was confirmed via contrastinjection and coronary venogram. Furthermore, measurement of theretroperfusion pressure (38.1±1.6 mmHg during therapy vs. 20.9±1.7 mmHgat baseline) in the LAD vein, distal to the tip of the SARP catheter,indicated that we achieved an ideal pressure (<50 mmHg), necessary toavoid myocardial edema and hemorrhage. Previous studies evaluating theeffects of machine-driven synchronized hypothermic retroperfusion indogs also reported a significant decrease in myocardial infarct sizealthough not to the magnitude reported in the present study. It is veryinteresting that autoretroperfusion appears to confer greater benefitthan machine-retroperfusion. In their study, Wakida and colleaguesreported an infarct size (relative to the area at risk) of 6.2±3.3% indogs treated with hypothermic retroperfusion, and 24.1±6.7% withnormothermic retroperfusion. Synchronized retroperfusion only permitsmyocardial retro flow in diastole and venous drainage during systole.The heart, however, is capable of distributing the blood flow of theischemic myocardium once blood is delivered through the coronary venoussystem, facilitating at the same time the wash out of toxic productswithout the need of intermittent occlusion of the coronary sinus. Thepresence of intervenous connections is important for the distribution offlow to different regions of the myocardium, minimizing the damage thatbuildup of intravascular pressure may cause.

Along with the significant reduction in infarct size, MH-SARP and SARPalone significantly reduced the incidence of ventricular arrhythmiasduring the reperfusion period, which correlated with outcome in humans.The presence of arrhythmias has been attributed to attenuation ofconduction, which usually occurs during ischemia and is pre-requisitefor re-entry. Recently, it has been postulated that mild hypothermiaprevents ischemia-induced conduction block and conduction velocityslowing by preserving gap junction coupling as well as sodium channelfunction. It is worth mentioning that large myocardial temperaturegradients can cause severe arrhythmias due to the dispersion of theaction potential, which underscores the importance of the degree ofhypothermia as an adjunctive therapy of myocardial ischemia. Anapproximate 1° C. reduction of the subendocardial temperaturesignificantly reduced the incidence of arrhythmic events during thereperfusion period. SARP alone also significantly reduced the presenceof arrhythmic events, although to a lesser degree (7.3±5.0 vs. 5.5±1.3).

Following the initiation of SARP, an increase in effluent PO₂ wasobserved. This somewhat paradoxical finding suggests a reduced oxygenuptake, which may be the result of cell death or conversion to aglycolytic ischemic metabolism. Support for the latter is provided bymarked increase in glucose uptake. These data demonstrate that the onsetof anaerobic glycolysis, as evidenced by lactate release across theischemic bed, may have contributed to the preservation of cellviability. Our main hypothesis was that mild hypothermia induces adecrease in metabolic demand and hence reduces myocardial cell deathduring the reperfusion period. The results obtained in this study withSARP alone, however, suggest that the primary benefit may be derived byoxygen delivery to the ischemic myocardium and removal of toxicbyproducts.

Although we did not find significant differences in EF, the low levelsof cTnI in the MH-SARP and SARP alone groups suggest cardiomyocytepreservation. Troponins are regulatory proteins integral to myocardialcontraction. The observed differences in EF may have been limited by therelatively short recovery period of four weeks.

Two biomarkers of myocardial infarction and reperfusion injury, miRNA-1and miRNA-133a, were strongly upregulated in plasma from the controlgroup. This upregulation of miRNAs in plasma is likely due to releasefrom the cytoplasm of cardiac cells. On the other hand, non-significantupregulation of miRNA-1 and miRNA-133a was found with implementation ofSARP alone or MH-SARP before reperfusion.

Study Limitations

SARP and MH-SARP in this study was applied almost immediately after theinitiation of the ischemic period. This schedule of treatment, however,is of little clinical relevance since therapy cannot always be appliedin patients within 30 min of the beginning of symptoms. Rather thanimitations of clinical flow, our intent here was to evaluate the therapyscientifically. Furthermore, the timing of implementation of SARP orMH-SARP needs to be taken into account before opening of the arterialocclusion. We believe that coronary sinus cannulation can beaccomplished within 5 min, which is on par with access to the sinus forlead implantation, and hence, would not significantly delay thedoor-to-balloon time. Furthermore, any small delay to thedoor-to-balloon time is unlikely to affect outcomes.

The relatively small sample size is a limitation of the study. The smallindividual differences in infarct size within each group, however,support our findings. Larger cohorts will be considered in futurestudies. Occlusion of the LAD artery was mechanically induced by ballooninflation in healthy animals with healthy coronary arteries. Futurestudies will consider the use of more clinically relevant animal modelssuch as animals fed with a high fat diet to induce atheroscleroticarteries.

As noted herein, unprecedented reductions in infarct size were achievedwith MH-SARP [(98.1±1.4%), 93.3% relative to control, p<0.0001] as wellas with SARP [(95.3±4.0%), 83.2% relative to control, p<0.0001]. Infarctsize with MH-SARP [median 1.8% (quartiles 1-3, 0.8-3.2%)] and SARP [3.9%(quartiles 1-3, 1.7-9.0%)] were significantly smaller than control[27.1% (quartiles 1-3, 25.5-29.6%)]. Cardiac troponin levels werereduced with MH-SARP after 30 min of reperfusion (1.4±0.8 ng/mL, p<0.01)and SARP (4.4±3.5 ng/mL, p<0.05) vs. control (14.2±9.0 ng/mL). miR-1(p<0.04) and miR-133a (p<0.02) levels increased approximately 7 times inthe control group after reperfusion injury, whereas in the SARP andMH-SARP groups the values after treatment were not statisticallydifferent from baseline. Significant recovery in the degree ofST-segment deviation was observed within 10 min of initiation oftherapy, as well as decrease in the incidence of arrhythmic events withMH-SARP (5.5±1.3, p<0.01) and SARP (7.3±5.0, p<0.01) vs. control(27.8±7.9) during reperfusion. Significant increase in PO₂, glucoseuptake, and release of lactate, were found with SARP and MH-SARPcompared with control.

The data indicate that SARP and MH-SARP preserve cellular integrity anddecrease myocardial infarct size. These findings warrant furtherinvestigation towards first in man translation, which may provide atherapeutic option to reduce RI substantially.

While various embodiments systems for selective auto-retroperfusionalong with regional mild hypothermia and methods for using the same havebeen described in considerable detail herein, the embodiments are merelyoffered by way of non-limiting examples of the disclosure describedherein. It will therefore be understood that various changes andmodifications may be made, and equivalents may be substituted forelements thereof, without departing from the scope of the disclosure.Indeed, this disclosure is not intended to be exhaustive or to limit thescope of the disclosure.

Further, in describing representative embodiments, the disclosure mayhave presented a method and/or process as a particular sequence ofsteps. However, to the extent that the method or process does not relyon the particular order of steps set forth herein, the method or processshould not be limited to the particular sequence of steps described.Other sequences of steps may be possible. Therefore, the particularorder of the steps disclosed herein should not be construed aslimitations of the present disclosure. In addition, disclosure directedto a method and/or process should not be limited to the performance oftheir steps in the order written. Such sequences may be varied and stillremain within the scope of the present disclosure.

The invention claimed is:
 1. A system, comprising: a catheter forcontrolling blood perfusion pressure, the catheter comprising: a bodyhaving a plurality of orifices, each of the orifices in fluidcommunication with a lumen of the body, and at least one expandableballoon, each having an interior that is in fluid communication with thelumen, and adapted to move between an expanded configuration and adeflated configuration; a flow unit comprising at least one sensor andconfigured to regulate pressure of a bodily fluid and configured to beregulated by a remote module based upon data obtained by the at leastone sensor; and a regional hypothermia system operably coupled to thecatheter, the regional hypothermia system operable to reduce and/orregulate a temperature of the bodily fluid flowing therethrough.
 2. Thesystem of claim 1, wherein the regional hypothermia system is furtheroperable to reduce and/or regulate a temperature of a portion of amammalian body, the portion selected from the group consisting of avessel, a tissue, and an organ.
 3. The system of claim 1, wherein theregional hypothermia system comprises a heat exchanger configured toreduce and/or regulate the temperature of the bodily fluid.
 4. Thesystem of claim 1, wherein one or more components of the regionalhypothermia system uses a cooling product to reduce and/or regulate thetemperature of the bodily fluid.
 5. The system of claim 1, furthercomprising: one or more temperature sensors coupled to the catheter, theone or more temperature sensors operable to detect the temperature ofthe bodily fluid.
 6. The system of claim 5, further comprising theremote module in wired or wireless communication with the one or moretemperature sensors and operable to receive and process the detectedtemperature(s) to regulate, reduce, and/or increase the temperature ofthe bodily fluid by way of altering an operation of the regionalhypothermia system.
 7. The system of claim 1, further comprising: anarterial blood flow device comprising a proximal end, a distal endconfigured to couple with a proximal end of the flow unit, and aninterior extending between the proximal end and the distal end, whereinthe proximal end, the distal end and the interior each configured toallow arterial blood to flow therethrough.
 8. The system of claim 1,wherein the flow unit further comprises: an elongated body having anopen proximal end, an open distal end coupled with the open proximal endof the body of the catheter, an interior extending between the openproximal end and the open distal end of the elongated body, and achamber surrounding at least a portion of the elongated body, thechamber adapted to expand and deflate and comprising an interior and atleast one port in fluid communication with the interior of the chamberand adapted to couple with a fluid source, and wherein the remote moduleautomatically adjusts the flow unit to regulate the flow of pressure ofthe bodily fluid by automatically expanding or deflating the chamber ofthe elongated body based on the data gathered by the at least onesensor.
 9. The system of claim 8, wherein at least one of the at leastone sensors of the flow unit is adapted to transmit the gathered data tothe remote module.
 10. The system of claim 1, further comprising: aconnection assembly for providing a sterile environment, the connectionassembly comprising: a cover comprising a body portion, a limb componentextending from the body portion, and an interior extending between thebody portion and the limb component, the interior configured to encasethe distal end of the elongated body of the flow unit and the proximalend of the body of the catheter therein; at least one flushing port influid communication with a gas supply and the interior of the cover; andat least one valve in fluid communication with the interior of thecover, the at least one valve adapted to drain gas from within theinterior of the cover.
 11. A system, comprising: a catheter forcontrolling blood perfusion pressure, the catheter comprising: a bodyhaving a plurality of orifices, each of the orifices in fluidcommunication with a lumen of the body, and at least one expandableballoon having an interior that is in fluid communication with thelumen, and adapted to move between an expanded configuration and adeflated configuration; a flow unit for regulating the flow and pressureof a bodily fluid, the flow unit comprising: an elongated body having anopen proximal end, an open distal end coupled with the open proximal endof the body of the catheter, an interior extending between the openproximal end and the open distal end of the elongated body, and achamber surrounding at least a portion of the elongated body, thechamber adapted to expand and deflate and comprising an interior and atleast one port in fluid communication with the interior of the chamberand adapted to couple with a fluid source, and at least one sensordisposed at or near the distal end of the elongated body, each of the atleast one sensors adapted to gather data from the bodily fluid flowingthrough the interior of the elongated body; and a regional hypothermiasystem operably coupled to the catheter and/or the flow unit, theregional hypothermia system operable to reduce and/or regulate atemperature of the bodily fluid flowing through the system.
 12. Thesystem of claim 11, further comprising a source of arterial blood flowcomprising a proximal end, a distal end configured to couple with theproximal end of the elongated body of the flow unit, and an interiorextending between the proximal end and the distal end, the proximal end,the distal end and the interior each configured to allow arterial bloodto flow therethrough.
 13. The system of claim 11, in which at least oneof the at least one sensors of the flow unit is adapted to transmit thegathered data to a remote device.
 14. The system of claim 11, in whichthe catheter further comprises at least one sensor coupled with thedistal end of the body, each of the at least one sensors adapted togather data on the bodily fluid flowing through the lumen of thecatheter and transmit the gathered data to a remote device.
 15. Thesystem of claim 11, wherein the regional hypothermia system comprises aheat exchanger configured to reduce and/or regulate the temperature ofthe bodily fluid.
 16. The system of claim 11, further comprising: one ormore temperature sensors coupled to the catheter and/or the flow unit,the one or more temperature sensors operable to detect the temperatureof the bodily fluid.
 17. A flow unit, comprising: an elongated bodyhaving an open proximal end, an open distal end, an interior extendingbetween the open proximal end and the open distal end, and a chambersurrounding at least a portion of the elongated body, the chamberadapted to expand and deflate and comprising an interior and at leastone port in fluid communication with the interior of the chamber andadapted to couple with a fluid source; and at least one sensor disposedat or near the distal end of the elongated body, at least one of the atleast one sensors in communication with a remote device and adapted togather data relating to a bodily fluid flowing through the interior ofthe elongated body; wherein the flow unit is configured to be coupled toa catheter for controlling blood perfusion pressure; and wherein theflow unit is further configured for operation in connection with aregional hypothermia system operably coupled to the catheter and/or theflow unit, the regional hypothermia system operable to reduce and/orregulate a temperature of the bodily fluid flowing therethrough.
 18. Theflow unit of claim 17, wherein one or more of the at least one sensorsis adapted to transmit the gathered data to a remote device.
 19. Theflow unit of claim 17, wherein a section of the interior of theelongated body associated with the portion surrounded by the chambercomprises a first diameter when the chamber is deflated and a seconddiameter when the chamber in expanded, the second diameter being lessthan the first diameter.
 20. The flow unit of claim 17, wherein when thechamber is expanded, the interior of the chamber is adapted to exert acompressive force on the portion of elongated body surrounded thereby.